Boron-Containing Small Molecules as Anti-Inflammatory Agents

ABSTRACT

Compounds and methods of treating anti-inflammatory conditions are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Pat. App. No.61/034,371, filed Mar. 6, 2008, U.S. Provisional Pat. App. No.61/052,637, filed May 12, 2008, U.S. Provisional Pat. App. No.61/094,406, filed Sep. 4, 2008, U.S. Provisional Pat. App. No.61/105,990, filed Oct. 16, 2008, U.S. Provisional Pat. App. No.61/110,903, filed Nov. 3, 2008, U.S. Provisional Pat. App. No.61/143,700, filed Jan. 9, 2009, and U.S. Provisional Pat. App. No.61/148,731, filed Jan. 30, 2009, each of which is incorporated byreference in its entirety for all purposes.

BACKGROUND FOR THE INVENTION

Irregular inflammation is a major component of a wide range of humandiseases. People suffering from degenerative disorders often exhibitexcess levels of pro-inflammatory regulators in their blood. One type ofsuch pro-inflammatory regulators are cytokines including IL-1α, β, IL-2,IL-3, IL-6, IL-7, IL-9, IL-112, IL-17, IL-18, IL-23, TNF-α, LT, LIF,Oncostatin, and IFNc1α, β, γ.

A non-limiting list of common medical problems that are directly causedby inflammatory cytokines include: arthritis where inflammatorycytokines can lead to lesions in the synovial membrane and destructionof joint cartilage and bone; kidney failure where inflammatory cytokinesrestrict circulation and damage nephrons; lupus where inflammatorycytokines exacerbate immune complex deposition and damage; asthma whereinflammatory cytokines close the airway; psoriasis where inflammatorycytokines induce dermatitis; pancreatitis where inflammatory cytokinesinduce pancreatic cell injury; allergy where inflammatory cytokinesinduce vasopermeability and congestion; fibrosis where inflammatorycytokines attack traumatized tissue; surgical complications whereinflammatory cytokines prevent healing; anemia where inflammatorycytokines attack erythropoietin production; and fibromyalgia whereinflammatory cytokines are elevated in fibromyalgia patients.

Other diseases associated with chronic inflammation include cancer;heart attack where chronic inflammation contributes to coronaryatherosclerosis; Alzheimer's disease where chronic inflammation destroysbrain cells; congestive heart failure where chronic inflammation causesheart muscle wasting; stroke where chronic inflammation promotesthrombo-embolic events; and aortic valve stenosis where chronicinflammation damages heart valves. Arteriosclerosis, osteoporosis,Parkinson's disease, infection, inflammatory bowel disease includingCrohn's disease and ulcerative colitis as well as multiple sclerosis (atypical autoimmune inflammatory-related disease) are also related toinflammation (Bebo, B. F., Jr., J Neurosci Res, 45: 340-348, (1996);Mennicken, F., Trends Pharmacol Sci, 20: 73-78, (1999); Watanabe, T, IntJ Cardiol, 66 Suppl 1: S45-53; discussion S55, (1998); Sullivan, G. W.,J Leukoc Biol, 67: 591-602, (2000); Franceschi, C., Ann N Y Acad Sci,908: 244-254, (2000); Rogers, J, Ann N Y Acad Sci, 924: 132-135, (2000);Li, Y. J., Hum Mol Genet, 12: 3259-3267, (2003); Maccarrone, M., CurrDrug Targets Inflamm Allergy, 1: 53-63, (2002); Lindsberg, P. J.,Stroke, 34: 2518-2532, (2003); DeGraba, T. J., Adv Neurol, 92: 29-42,(2003); . Ito, H., Curr Drug Targets Inflamm Allergy, 2: 125-130,(2003); von der Thusen, J. H., Pharmacol Rev, 55: 133-166, (2003);Schmidt, M. I., Clin Chem Lab Med, 41: 1120-1130, (2003); Virdis, A.,Curr Opin Nephrol Hypertens, 12: 181-187, (2003); Tracy, R. P., Int JClin Pract, Suppl 10-17, (2003); Haugeberg, G., Curr Opin Rheumatol, 15:469-475, (2003); Tanaka, Y., J Bone Miner Metab, 21: 61-66, (2003);Williams, J. D., Clin Exp Dermatol, 27: 585-590, (2002)). Some diseasesin advanced stages can be life threatening. Several methodologies areavailable for the treatment of such inflammatory diseases; the results,however, are generally unsatisfactory as evidenced by a lack of efficacyand drug related side effects associated therewith.

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) comprises Crohn's disease (CD) andulcerative colitis (UC), both of which are idiopathic chronic diseasesoccurring with an increasing frequency in many parts of the world. Inthe United States, more than 600,000 are affected every year. IBD caninvolve either small bowel, large bowel, or both. CD can involve anypart of the gastrointestinal tract, but most frequently involves thedistal small bowel and colon. It either spares the rectum, or causesinflammation or infection with drainage around the rectum. UC usuallycauses ulcers in the lower part of the large intestine, often startingat the rectum. Patients with IBD have defective intestinal epithelialbarrier function, which allows bacterial colonization of the epithelia.As a result, bacterial products and pro-inflammatory cytokines (TNF-α,IL-1 and IL-6) cause persistent inflammatory stimulation. Bacterialantigens are introduced into the immune system by mucosal dendriticcells and macrophases. In response, intestinal phagocytes (mainlymonocytes and neutrophils) proliferate and increase expression andsecretion of pro-inflammatory cytokines. Symptoms vary but may includediarrhea, fever, and pain. Patients with prolonged UC are at anincreased risk of developing colon cancer. There is currently nosatisfactory treatment, as the cause for IBD remains unclear althoughinfectious and immunologic mechanisms have been proposed. IBD treatmentsaim at controlling inflammatory symptoms, conventionally usingcorticosteroids, aminosalicylates and standard immunosuppressive agentssuch as azathioprine (6-mercaptopurine), methotrexate and ciclosporine.Of these, the only disease-modifying therapies are the immunosuppressiveagents azathioprine and methotrexate, both of which have a slow onset ofaction and only a moderate efficacy. Long-term therapy may cause liverdamage (fibrosis or cirrhosis) and bone marrow suppression. Alsopatients often become refractory to such treatment. Other therapeuticregimes merely address symptoms (Rutgeerts, P. A, J GastroenterolHepatol, 17 Suppl: S176-185 (2002); Rutgeerts, P., Aliment PharmacolTher, 17: 185-192 (2003)).

Psoriasis

Psoriasis is one of the most common immune-mediated chronic skindiseases that comes in different forms and varied levels of severity,affecting approximately 2% of the population or more than 4.5 millionpeople in the United States of which 1.5 million are considered to havea moderate to severe form of the disease. Ten to thirty percent ofpatients with psoriasis also develop a form of arthritis—psoriaticarthritis, which damages the bone and connective tissue around thejoints. Psoriasis appears as patches of raised red skin covered by aflaky white buildup. It may also have a pimple-ish (pustular psoriasis)or burned (erythrodermic) appearance. Psoriasis may also cause intenseitching and burning. Patients suffer psychologically as well asphysically. Several modalities are currently available for treatment ofpsoriasis, including topical treatment, phototherapy, and systemicapplications. However, they are generally considered to be only diseasesuppressive and disease modifying; none of them are curative. Moreover,many treatments are either cosmetically undesirable, inconvenient forlong-term use, or associated with significant toxicity.

There are several types of psoriasis. Plaque psoriasis (psoriasisvulgaris) is the most common form of psoriasis. It affects 80 to 90% ofpeople with psoriasis. Plaque psoriasis typically appears as raisedareas of inflamed skin covered with silvery white scaly skin. Theseareas are called plaques. Flexural psoriasis (inverse psoriasis) appearsas smooth inflamed patches of skin. It occurs in skin folds,particularly around the genitals (between the thigh and groin), thearmpits, under an overweight stomach (pannus), and under the breasts(inframammary fold). It is aggravated by friction and sweat, and isvulnerable to fungal infections. Guttate psoriasis is characterized bynumerous small oval (teardrop-shaped) spots. These numerous spots ofpsoriasis appear over large areas of the body, such as the trunk, limbs,and scalp. Guttate psoriasis is associated with streptococcal throatinfection. Pustular psoriasis appears as raised bumps that are filledwith non-infectious pus (pustules). The skin under and surroundingpustules is red and tender. Pustular psoriasis can be localised,commonly to the hands and feet (palmoplantar pustulosis), or generalisedwith widespread patches occurring randomly on any part of the body. Nailpsoriasis produces a variety of changes in the appearance of finger andtoe nails. These changes include discolouring under the nail plate,pitting of the nails, lines going across the nails, thickening of theskin under the nail, and the loosening (onycholysis) and crumbling ofthe nail. Psoriatic arthritis involves joint and connective tissueinflammation. Psoriatic arthritis can affect any joint but is mostcommon in the joints of the fingers and toes. This can result in asausage-shaped swelling of the fingers and toes known as dactylitis.Psoriatic arthritis can also affect the hips, knees and spine(spondylitis). About 10-15% of people who have psoriasis also havepsoriatic arthritis. Erythrodermic psoriasis involves the widespreadinflammation and exfoliation of the skin over most of the body surface.It may be accompanied by severe itching, swelling and pain. It is oftenthe result of an exacerbation of unstable plaque psoriasis, particularlyfollowing the abrupt withdrawal of systemic treatment. This form ofpsoriasis can be fatal, as the extreme inflammation and exfoliationdisrupt the body's ability to regulate temperature and for the skin toperform barrier functions.

With increased understanding of the biological properties of psoriasisover the past two decades, biologic therapies targeting the activity ofT lymphocytes and cytokines responsible for the inflammatory nature ofthis disease have become available. Currently, drugs prescribed forpsoriasis include TNF-α inhibitors initially used for rheumatoidarthritis (RA) treatment, ENBREL® (etanercept), REMICADE® (infliximab)and HUMIRA® (adalimumab), and T-cell inhibitor AMEVIVE® (alefacept) fromBiogen approved in 2002 and RAPTIVA® (efalizumab) from Genentech/Xomaapproved in 2003 (Weinberg, J. M., J Drugs Dermatol, 1: 303-310,(2002)). AMEVIVE® (alefacept) is an immunoglobulin fusion proteincomposed of the first extracellular domain of human LFA-3 fused to thehinge, C(H)2 and C(H)3 domains of human IgG(1). It inhibits T cellproliferation through NK cells (Cooper, J. C., Eur J Immunol, 33:666-675, (2003)). RAPTIVA® is also known as anti-CD 11a, a humanizedmonoclonal antibody which targets the T cell adhesion molecule,leukocyte function-associated antigen-1 (LFA-1). Prevention of LFA-1binding to its ligand (ICAM-1, intercellular adhesion molecule-1)inhibits lymphocyte activation and migration, resulting in a decreasedlymphocyte infiltration, thereby limiting the cascade of eventseventually leading to the signs and symptoms of psoriasis (Cather, J.C., Expert Opin Biol Ther, 3: 361-370, (2003)). Potential side effectsfor current TNF-α inhibitors of the prior art, however, are severe,including development of lymphoma (Brown, S. L., Arthritis Rheum, 46:3151-3158, (2002)), worsening congestive heart failure, resulting in aserious infection and sepsis, and exacerbations of multiple sclerosisand central nervous system problems (Weisman, M. H., J Rheumatol Suppl,65: 33-38, (2002); Antoni, C., Clin Exp Rheumatol, 20: S152-157,(2002)). While side effects of the T-cell inhibitor of AMEVIVE®/RAPTIVA®may be more tolerable in psoriasis treatment, RAPTIVA® is animmunosuppressive agent. Immunosuppressive agents have the potential toincrease the risk of infection, reactivate latent, chronic infections orincrease the risk of cancer development.

Although many advances have been made in the understanding of thebiological properties of psoriasis over the past two decades and anunconventional treatment for psoriasis has become available as describedabove, much of the suffering it produces is still not adequatelyaddressed. A survey of over 40,000 American patients with psoriasisperformed by the National Psoriasis Foundation in 1998 showed 79% of theyounger patients felt frustrated by the ineffectiveness of theirtreatment. Of those with severe disease, 32% felt their treatment wasnot aggressive enough (Mendonca, C. O., Pharmacol Ther, 99: 133-147,(2003); Schon, M. P., J Invest Dermatol, 112: 405-410, (1999)).

Rheumatoid Arthritis

Rheumatoid arthritis (RA) represents another example of troublesomeinflammatory disorders. It is a common chronic inflammatory-relateddisease characterized by chronic inflammation in the membrane lining(the synovium) of the joints and/or other internal organs. Theinflammatory cells can also invade and damage bone and cartilage. Thejoint involved can lose its shape and alignment, resulting in loss ofmovement. Patients with RA have pain, stiffness, warmth, redness andswelling in the joint, and other systemic symptoms like fever, fatigue,and anemia. Approximately 1% of the population or 2.1 million in theU.S. are currently affected, of which more are women (1.5 million) thanmen (0.6 million). The pathology of RA is not fully understood althoughthe cascade of improper immunological reactions has been postulated as amechanism. Conventional treatment is unfortunately inefficient in RA(Bessis, N., J Gene Med, 4: 581-591, (2002)) (29). The disease does notrespond completely to symptomatic medications including corticosteroidsand non-steroidal anti-inflammatory drugs (NSAIDs) used since the 1950s.Also, these medications carry a risk of serious adverse effects. Thetherapeutic effects of the disease-modifying antirheumatic drugs(DMARDs) such as Methotrexate (MTX) are often inconsistent andshort-lived.

The role of the cytokine network in mediating inflammation and jointdestruction in RA has been extensively investigated in recent years. Inaddition to TNF-α, IL-1 plays a pivotal role in the pathogenesis and theclinical manifestations of RA (54). The ability of IL-1 to driveinflammation and joint erosion and to inhibit tissue repair processeshas been clearly established in in vitro systems and in animal models,and alleviation of inflammatory symptoms in RA patients has beenachieved by blockage of IL-1 (Bresnihan, B., Arthritis Rheum, 41:2196-2204, (1998)). IL-6 is a multifunctional cytokine that regulatesthe immune response, hematopoiesis, the acute phase response, andinflammation. Deregulation of IL-6 production is implicated in thepathology of several diseases including RA. A therapeutic approach toblock the IL-6 signal has been carried out by using humanized anti-IL-6Rantibody for RA among other diseases (Ito, H., Curr Drug Targets InflammAllergy, 2: 125-130, (2003); Ishihara, K Cytokine Growth Factor Rev, 13:357-368, (2002)). IL-10 is an anti-inflammatory cytokine. ExpressingIL-10 has been shown to prevent arthritis or ameliorate the disease inanimal models (57, 58). While it is obvious that cytokines such asTNF-α, IL-1, IL-6 and IL-10 have independent roles, they act in concertin mediating certain pathophysiological processes in RA. The finding ofa class of molecules described in this invention, which are able tomodulate these different cytokines, will result in dramatic therapeuticprogress in the treatment of RA.

A new class of biologic DMARDs (disease-modifying antirheumatic drugs)for the treatment of RA has recently been developed based on anunderstanding of the role of cytokines, TNF-α and IL-1, in theinflammatory process. The FDA has approved several such DMARDs includingENBREL® (etanercept) from Immunex/Amgen Inc. in 1998, REMICADE®(infliximab) from Centocor/Johnson & Johnson, HUMIRA® (adalimumab) fromAbbott Laboratories Inc. in 2002, and KINERET® (anakinra) from Amgen in2001. ENBREL® is a soluble TNF receptor (TNFR) recombinant protein.REMICADE® is a humanized mouse (chimeric) anti-TNF-α monoclonalantibody. HUMIRA® is a fully human anti-TNF monoclonal antibody createdusing phage display technology resulting in an antibody withhuman-derived heavy and light chain variable regions and human IgG1:kconstant regions. All these 3 protein-based drugs target and bind toTNF-α to block the effects of TNF-α. KINERET® is a recombinant IL-1receptor antagonist, which is similar to native human IL-1Ra, except forthe addition of a single methionine residue at its amino terminus.KINERET® blocks the biologic activity of IL-1 by competitivelyinhibiting IL-1 binding to the IL-1 type I receptor (IL-1RI) andconsequently reducing the pro-inflammatory effects of IL-1.

Multiple Sclerosis

Multiple Sclerosis (MS) is an autoimmune disease diagnosed in 350,000 to500,000 people in the United States. Multiple areas of inflammation andloss of myelin in the brain and spinal cord signify the disease.Patients with MS exhibit varied degrees of neurological impairmentdepending on the location and extent of the loss of the myelin. There isevidence that the expression of chemokines (IL-8 family members) duringCNS autoimmune inflammation is regulated by some pro-inflammatorycytokines, such as TNF (Glabinski, A. R., Scand J Immunol, 58: 81-88,(2003)). The roles of other pro-/anti-inflammatory cytokines such asIL-1.beta., IL-6 and IL-10 were also confirmed in EAE animal models(Diab, A., J Neuropathol Exp Neurol, 56: 641-650, (1997); Samoilova, E.B., J Immunol, 161: 6480-6486, (1998); Robertson, J., J Cell Biol, 155:217-226, (2001)) as well as in humans (de Jong, B. A., J Neuroimmunol,126: 172-179, (2002)). IL-1β is present in MS lesions. IL-1 receptorantagonist (IL-1Ra) moderates the induction of experimental autoimmuneencephalomyelitis (EAE). Increased risk of MS has been seen inindividuals with High IL-1 (3 over IL-1Ra production ratio and high TNFover IL-10 production ratio (de Jong, B. A., J Neuroimmunol, 126:172-179, (2002)). Common symptoms of MS include fatigue, weakness,spasticity, balance problems, bladder and bowel problems, numbness,vision loss, tremors and depression. Current treatment of MS onlyalleviates symptoms or delays the progression of disability, and severalnew treatments for MS including stem cell transplantation and genetherapy are conservatory (Fassas, A., Blood Rev, 17: 233-240, (2003);Furlan, R., Curr Pharm Des, 9: 2002-2008, (2003)). While anti-TNFantibodies have shown protective effects in experimental autoimmuneencephalomyelitis (EAE), they aggravate the disease in MS patients,suggesting that inhibition of TNF-α alone is not sufficient (Ghezzi, P.,Neuroimmunomodulation, 9: 178-182, (2001)).

Neurodegenerative Disorders

Alzheimer's disease (AD) and Parkinson's disease (PK) are the two mostcommon neurodegenerative disorders. AD seriously affects a person'sability to carry out daily activities. It involves the parts of thebrain that control thought, memory, and language. About 4 millionAmericans, usually after age 60, are estimated to suffer from AD.

PK is a progressive disorder of the central nervous system affectingover 1.5 million people in the United States. Clinically, the disease ischaracterized by a decrease in spontaneous movements, gait difficulty,postural instability, rigidity and tremor. PK is caused by thedegeneration of the pigmented neurons in the substantia nigra of thebrain, resulting in decreased dopamine availability. The causes of theseneurodegenerative disorders are unknown and there is currently no curefor the disease.

Thus, novel approaches for the treatment of the above and otherinflammatory-related diseases are needed. Although inflammatory-relateddisease mechanisms remain unclear and often vary from each other,dysfunction of the immune system caused by deregulation of cytokines hasbeen demonstrated to play an important role in the initiation andprogression of inflammation (Schon, M. P., J Invest Dermatol, 112:405-410, (1999); Andreakos, E. T., Cytokine Growth Factor Rev, 13:299-313, (2002); Najarian, D. J., J Am Acad Dermatol, 48: 805-821,(2003)).

Post-Radiotherapy Related Inflammation:

Radiation damage related inflammatory diseases to the rectum and sigmoidcolon are most common complications with radiation therapy for cancersin the pelvic region, which include cancers of the cervix, uterus,prostate, bladder, and testes. Radiation proctosigmoiditis is the mostcommon clinically apparent form of colonic damage after pelvicirradiation with an incidence of 5% to 20%. Patients typically exhibitsymptoms of tenesmus, bleeding, low-volume diarrhea, and rectal pain.Rarely, low-grade obstruction or fistulous tracts into adjacent organsmay develop.

Cytokines can be generally classified into 3 types: pro-inflammatory(IL-1α, β, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, IL-23,TNF-α, LT, LIF, Oncostatin, and IFNc1α, β, γ); anti-inflammatory (IL-4,IL-10, IL-11, W-13 and TGF-β); and chemokines (IL-8, Gro-α, MIP-1,MCP-1, ENA-78, and RANTES).

Tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) areproinflammatory cytokines that mediate inflammatory responses associatedwith infectious agents and other cellular stresses. Overproduction ofcytokines such as IL-1 and TNF-α is believed to underlie the progressionof many inflammatory diseases including rheumatoid arthritis (RA),Crohn's disease, inflammatory bowel disease, multiple sclerosis,endotoxin shock, osteoporosis, Alzheimer's disease, congestive heartfailure, and psoriasis among others (Dinarello, C. A. et al., Rev.Infect. Diseases 1984, 6:51; Salituro et al., Curr. Med. Chem. 1999,6:807-823; Henry et al., Drugs Fut. 1999, 24:1345-1354). An acceptedtherapeutic approach for potential drug intervention in these conditionsis the reduction of proinflammatory cytokines such as TNF-α (alsoreferred to as TNFa) and interleukin-1β (IL-1b).

Phosphodiesterase4

The cyclic nucleotide specific phosphodiesterases (PDEs) represent afamily of enzymes that catalyze the hydrolysis of various cyclicnucleoside monophosphates (including cAMP and cGMP). These cyclicnucleotides act as second messengers within cells, and as messengers,carry impulses from cell surface receptors having bound various hormonesand neurotransmitters. PDEs act to regulate the level of cyclicnucleotides within cells and maintain cyclic nucleotide homeostasis bydegrading such cyclic mononucleotides resulting in termination of theirmessenger role.

PDE enzymes can be grouped into eleven families according to theirspecificity toward hydrolysis of cAMP or cGMP, their sensitivity toregulation by calcium, calmodulin or cGMP, and their selectiveinhibition by various compounds. For example, PDE 1 is stimulated byCa²⁺/calmodulin. PDE 2 is cGMP-dependent, and is found in the heart andadrenals. PDE 3 is cGMP-dependent, and inhibition of this enzyme createspositive inotropic activity. PDE 4 is cAMP specific, and its inhibitioncauses airway relaxation, antiinflammatory and antidepressant activity.PDE 5 appears to be important in regulating cGMP content in vascularsmooth muscle, and therefore PDE 5 inhibitors may have cardiovascularactivity. Since the PDEs possess distinct biochemical properties, it islikely that they are subject to a variety of different forms ofregulation.

PDE4 is distinguished by various kinetic properties including lowMichaelis constant for cAMP and sensitivity to certain drugs. The PDE4enzyme family consists of four genes, which produce 4 isoforms of thePDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D [See: Wang et al.,Expression, Purification, and Characterization of human cAMP-SpecificPhosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Res.Comm., 234, 320 324 (1997)] In addition, various splice variants of eachPDE4 isoform have been identified.

PDE4 isoenzymes are localized in the cytosol of cells and areunassociated with any known membranous structures. PDE4 isoenzymesspecifically inactivate cAMP by catalyzing its hydrolysis to adenosine5′-monophosphate (AMP). Regulation of cAMP activity is important in manybiological processes, including inflammation and memory. Inhibitors ofPDE4 isoenzymes such as rolipram, piclamilast, CDP-840 and ariflo arepowerful antiinflammatory agents and therefore may be useful in treatingdiseases where inflammation is problematic such as asthma or arthritis.Further, rolipram improves the cognitive performance of rats and mice inlearning paradigms.

Compounds which can inhibit the biological moieties described above, ortreat diseases involving those biological moieties, would be asignificant advance in the art.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides a compound of the invention.In an exemplary embodiment, the compound is described herein or apharmaceutically acceptable salt thereof. In an exemplary embodiment,the compound is according to a formula described herein. In an exemplaryembodiment, the compound is a member selected from D1, D2, D3, D4, D5,D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16, D17, D18, D19, D20,D21, D22, D23, D24, D25, D26, D27, D28, D29, D30, D31, D32, D33, D34,D35, D36, D37, D38, D39, D40, D41, D42, D43, D44, D45, D46, D47, D48,D49, D50, D51, D52, D53, D54, D55, D56, D57, D58, D59, D60, D61, D62,D63, D64, D65, D66, D67, D68, D69, D70, D71, D72, D73, D74, D75, D76,D77, D78, D79, D80, D81, D82, D83, D84, D85, D86, D87, D88, D89, D90,D91, D92, D93, D94, D95, D96, D97, D98, D99, D100, D101, D102, D103,D104, D105, D106, D107, D108, D109, D110, D111, D112, D113, D114, D115,D116, D117, D118, D119, D120, D121, D122, D123, D124, D125, D126, D127,D128, D129, D130, D131, D132, D133, D134, D135, D136, D137, D138, D139,D140, D141, D142, D143, D144, D145, D146, D147, D148, D149, D150, D151,D152, D153, D154, D155, D156, D157, D158, D159, D160, D161, D162, D163,D164, D165, D166, D167, D168, D169, D170, D171, D172, D173, D174, D175,D176, D177, D178, D179, D180, D181, D182, D183, D184, D185, D186, D187,D188, D189, D190, D191, D192, D193, D194, D195, D196, D197, D198, D199,D200, D201, D202, D203, D204, D205, D206, D207, D208, D209, D210, D211,D212, D213, D214, D215, D216, D217, D218, D219, D220, D221, D222, D223,D224, D225, D226, D227, D228 and D229.

In a second aspect, the invention provides a compound, and saltsthereof, having a structure according to the formula:

wherein R* is a member selected from H, a negative charge and apositively charged counterion. X is a member selected from CR^(a),CR^(b) and N. R^(a) is a member selected from CN, —C(O)NR¹R², and—C(O)OR³. R^(b) and R^(c) are members independently selected from H,OR⁴, NR⁴R⁵, SR⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)₂NR⁴R⁵, —C(O)R⁴, —C(O)OR⁴,—C(O)NR⁴R⁵, nitro, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl,wherein each R¹, R², R⁴ and R⁵ are members independently selected fromH, nitro, halogen, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl. R³is a member selected from H and substituted or unsubstituted alkyl.There is a proviso that R¹ and R², together with the atoms to which theyare attached, are optionally combined to form a 5- to 7-memberedsubstituted or unsubstituted heterocycloalkyl ring. There is a provisothat R⁴ and R⁵, together with the atoms to which they are attached, areoptionally combined to form a 5- to 7-membered substituted orunsubstituted heterocycloalkyl ring. There is a proviso R^(b) and R^(c)cannot both be H. There is a proviso that R^(a) and R^(b) are optionallyjoined to form a 5- to 8-membered ring comprising two oxo moieties.

The invention also provides pharmaceutical formulations, and methods ofmaking and using the compounds described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 displays exemplary compounds of the invention.

FIG. 2 displays exemplary compounds of the invention.

FIG. 3 displays exemplary compounds of the invention.

FIG. 5 displays exemplary compounds of the invention.

FIG. 6 displays exemplary compounds of the invention.

FIG. 7 displays exemplary compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions and Abbreviations

As used herein, the singular forms “a,” “an”, and “the” include pluralreferences unless the context clearly dictates otherwise. For example,reference to “an active agent” includes a single active agent as well astwo or more different active agents in combination. It is to beunderstood that present teaching is not limited to the specific dosageforms, carriers, or the like, disclosed herein and as such may vary.

The abbreviations used herein generally have their conventional meaningwithin the chemical and biological arts.

The following abbreviations have been used: aq.—aqueous;HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; EDCI—N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride; m-CPBA—3-chloroperoxybenzoic acid; equiv—equivalent;DIAD—diisopropyl azodicarboxylate; DMF—N,N-dimethylformamide;DMSO—dimethylsulfoxide; AcOH—acetic acid; NaCNBH₃—sodiumcyanoborohydride; Rt—room temperature; THF—tetrahydrofuran;Boc₂O—di-tert-butyl dicarbonate; MeOH—methanol; EtOH—ethanol;TFA—trifluoroacetic acid; DIPEA—N,N-diisopropylethylamine;PrOH—1-propanol; i-PrOH—2-propanol; mp—melting point;NMM—N-methylmorpholine; B₂pin₂—bis(pinacolato)diboron; O/N—overnight;BzOOH—benzoyl peroxide; THP—tetrahydropyranyl; Ac—acetyl;PTSA—para-toluene sulfonic acid; Pyr.—Pyridine; Cbz—benzyloxycarbonyl;MPM—p-methoxybenzyl; DHP—dihydropyran; CSA—camphor sulfonic acid;CTAB—cetyltrimethylammonium bromide; sat.—saturated; Cy—cyclohexyl;Ph—phenyl; Ar—aryl.

“Compound of the invention,” as used herein refers to the compoundsdiscussed herein, salts (such as pharmaceutically acceptable salts),prodrugs, solvates and hydrates of these compounds.

“Inhibiting” and “blocking,” are used interchangeably herein to refer tothe partial or full blockade of the expression of a pro-inflammatorycytokine by a method of the invention, which leads to a decrease in theamount of the cytokine in the animal.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents, which would result from writing thestructure from right to left, e.g., —CH₂O— is intended to also recite—OCH₂—.

The term “poly” as used herein means at least 2. For example, apolyvalent metal ion is a metal ion having a valency of at least 2.

“Moiety” refers to the radical of a molecule that is attached to anothermoiety.

The symbol

whether utilized as a bond or displayed perpendicular to a bond,indicates the point at which the displayed moiety is attached to theremainder of the molecule.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). In some embodiments, the term “alkyl” means astraight or branched chain, or combinations thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals. Examples of saturated hydrocarbon radicals include, but arenot limited to, groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers.

The term “unsubstituted alkyl” encompasses straight or branched chainsaturated hydrocarbon radicals. Examples of saturated hydrocarbonradicals include, but are not limited to, groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the present invention. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom. In someembodiments, the term “heteroalkyl,” by itself or in combination withanother term, means a stable straight or branched chain, or combinationsthereof, consisting of the stated number of carbon atoms and at leastone heteroatom. In an exemplary embodiment, the heteroatoms can beselected from the group consisting of B, O, N and S, and wherein thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenheteroatom may optionally be quaternized. The heteroatom(s) B, O, N andS may be placed at any interior position of the heteroalkyl group or atthe position at which the alkyl group is attached to the remainder ofthe molecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃. Similarly, the term “heteroalkylene” byitself or as part of another substituent means a divalent radicalderived from heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings(preferably from 1 to 3 rings), which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms. In an exemplary embodiment, theheteroatom is selected from B, N, O, and S, wherein the nitrogen andsulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. A heteroaryl group can be attached to theremainder of the molecule through a heteroatom. Non-limiting examples ofaryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, 6-quinolyl, dioxaborolane, dioxaborinane and dioxaborepane.Substituents for each of the above noted aryl and heteroaryl ringsystems are selected from the group of acceptable substituents describedbelow.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes those radicals in whichan aryl group is attached through the next moiety to the rest of themolecule. Thus, the term “arylalkyl” is meant to include those radicalsin which an aryl group is attached to an alkyl group (e.g., benzyl,1-(3-nitrophenyl)ethyl and the like). A substituent such as benzyl or1-(3-nitrophenyl)ethyl can also be represented by ‘substituted alkyl’wherein the ethyl radical is substituted with a 3-nitrophenyl moiety.The term “aryloxy” is meant to include those radicals in which an arylgroup is attached to an oxygen atom. The term “aryloxyalkyl” is meant toinclude those radicals in which an aryl group is attached to an oxygenatom which is then attached to an alkyl group (e.g., phenoxymethyl,3-(1-naphthyloxy)propyl, and the like).

For brevity, the term “heteroaryl” when used in combination with otherterms (e.g., heteroaryloxy, heteroarylthioxy, heteroarylalkyl) includesthose radicals in which a heteroaryl group is attached through the nextmoiety to the rest of the molecule. Thus, the term “heteroarylalkyl” ismeant to include those radicals in which a heteroaryl group is attachedto an alkyl group (e.g., pyridylmethyl and the like). The term“heteroaryloxy” is meant to include those radicals in which a heteroarylgroup is attached to an oxygen atom. The term “heteroaryloxyalkyl” ismeant to include those radicals in which an aryl group is attached to anoxygen atom which is then attached to an alkyl group. (e.g.,2-pyridyloxymethyl and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″,—SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NR′″″—C(NR′R″R′″)═NR″″, —NR″″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR″SO₂R′, —CN, —NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R′, R″, R′″, R″″and R′″″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., arylsubstituted with 1-3 halogens, substituted or unsubstituted alkyl,alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″, R″″ and R′″″groups when more than one of these groups is present. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R″is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are generically referredto as “aryl group substituents.” The substituents are selected from, forexample: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR′″″—C(NR′R″R′″)═NR″″,—NR″″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR″SO₂R′, —CN,—NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in anumber ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R′″, R″″ and R′″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,R″″ and R′″″ groups when more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)-U-, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituents R, R′, R″ and R′″ are preferably independently selectedfrom hydrogen or substituted or unsubstituted (C₁-C₆)alkyl.

“Ring” as used herein, means a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. A ringincludes fused ring moieties. The number of atoms in a ring is typicallydefined by the number of members in the ring. For example, a “5- to7-membered ring” means there are 5 to 7 atoms in the encirclingarrangement. Unless otherwise specified, the ring optionally includes aheteroatom. Thus, the term “5- to 7-membered ring” includes, for examplephenyl, pyridinyl and piperidinyl. The term “5- to 7-memberedheterocycloalkyl ring”, on the other hand, would include pyridinyl andpiperidinyl, but not phenyl. The term “ring” further includes a ringsystem comprising more than one “ring”, wherein each “ring” isindependently defined as above.

As used herein, the term “heteroatom” includes atoms other than carbon(C) and hydrogen (H). Examples include oxygen (O), nitrogen (N) sulfur(S), silicon (Si), germanium (Ge), aluminum (Al) and boron (B).

The symbol “R” is a general abbreviation that represents a substituentgroup that is selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted cycloalkyl and substituted or unsubstitutedheterocycloalkyl groups.

By “effective” amount of a drug, formulation, or permeant is meant asufficient amount of a active agent to provide the desired local orsystemic effect. A “Topically effective,” “Cosmetically effective,”“pharmaceutically effective,” or “therapeutically effective” amountrefers to the amount of drug needed to effect the desired therapeuticresult.

“Topically effective” refers to a material that, when applied to theskin, nail, hair, claw or hoof produces a desired pharmacological resulteither locally at the place of application or systemically as a resultof transdermal passage of an active ingredient in the material.

“Cosmetically effective” refers to a material that, when applied to theskin, nail, hair, claw or hoof, produces a desired cosmetic resultlocally at the place of application of an active ingredient in thematerial.

The terms “pharmaceutically acceptable salts” or “a salt thereof” aremeant to include salts of the compounds of the invention which areprepared with relatively nontoxic acids or bases, depending on theparticular substituents found on the compounds described herein. Whencompounds of the present invention contain relatively acidicfunctionalities, base addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredbase, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable base addition salts include sodium,potassium, calcium, ammonium, organic amino, or magnesium salt, or asimilar salt. When compounds of the present invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, for example, Bergeet al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present inventioncontain both basic and acidic functionalities that allow the compoundsto be converted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompounds in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds or complexesdescribed herein readily undergo chemical changes under physiologicalconditions to provide the compounds of the present invention.Additionally, prodrugs can be converted to the compounds of the presentinvention by chemical or biochemical methods in an ex vivo environment.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the present invention. The graphic representations of racemic,ambiscalemic and scalemic or enantiomerically pure compounds used hereinare taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and brokenwedges are used to denote the absolute configuration of a stereocenterunless otherwise noted. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms areincluded.

Compounds of the invention can exist in particular geometric orstereoisomeric forms. The invention contemplates all such compounds,including cis- and trans-isomers, (−)- and (+)-enantiomers, (R)- and(S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, such as enantiomericallyor diastereomerically enriched mixtures, as falling within the scope ofthe invention. Additional asymmetric carbon atoms can be present in asubstituent such as an alkyl group. All such isomers, as well asmixtures thereof, are intended to be included in this invention.

Optically active (R)- and (S)-isomers and d and l isomers can beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If, for instance, a particular enantiomer of acompound of the present invention is desired, it can be prepared byasymmetric synthesis, or by derivatization with a chiral auxiliary,where the resulting diastereomeric mixture is separated and theauxiliary group cleaved to provide the pure desired enantiomers.Alternatively, where the molecule contains a basic functional group,such as an amino group, or an acidic functional group, such as acarboxyl group, diastereomeric salts can be formed with an appropriateoptically active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means known in the art, and subsequent recovery of thepure enantiomers. In addition, separation of enantiomers anddiastereomers is frequently accomplished using chromatography employingchiral, stationary phases, optionally in combination with chemicalderivatization (e.g., formation of carbamates from amines).

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable vehicle” refers to any formulation or carrier medium thatprovides the appropriate delivery of an effective amount of an activeagent as defined herein, does not interfere with the effectiveness ofthe biological activity of the active agent, and that is sufficientlynon-toxic to the host or patient. Representative carriers include water,oils, both vegetable and mineral, cream bases, lotion bases, ointmentbases and the like. These bases include suspending agents, thickeners,penetration enhancers, and the like. Their formulation is well known tothose in the art of cosmetics and topical pharmaceuticals. Additionalinformation concerning carriers can be found in Remington: The Scienceand Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins(2005) which is incorporated herein by reference.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable vehicle” refers to any formulation or carrier medium thatprovides the appropriate delivery of an effective amount of a activeagent as defined herein, does not interfere with the effectiveness ofthe biological activity of the active agent, and that is sufficientlynon-toxic to the host or patient. Representative carriers include water,oils, both vegetable and mineral, cream bases, lotion bases, ointmentbases and the like. These bases include suspending agents, thickeners,penetration enhancers, and the like. Their formulation is well known tothose in the art of cosmetics and topical pharmaceuticals. Additionalinformation concerning carriers can be found in Remington: The Scienceand Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins(2005) which is incorporated herein by reference.

“Pharmaceutically acceptable topical carrier” and equivalent terms referto pharmaceutically acceptable carriers, as described herein above,suitable for topical application. An inactive liquid or cream vehiclecapable of suspending or dissolving the active agent(s), and having theproperties of being nontoxic and non-inflammatory when applied to theskin, nail, hair, claw or hoof is an example of apharmaceutically-acceptable topical carrier. This term is specificallyintended to encompass carrier materials approved for use in topicalcosmetics as well.

The term “pharmaceutically acceptable additive” refers to preservatives,antioxidants, fragrances, emulsifiers, dyes and excipients known or usedin the field of drug formulation and that do not unduly interfere withthe effectiveness of the biological activity of the active agent, andthat is sufficiently non-toxic to the host or patient. Additives fortopical formulations are well-known in the art, and may be added to thetopical composition, as long as they are pharmaceutically acceptable andnot deleterious to the epithelial cells or their function. Further, theyshould not cause deterioration in the stability of the composition. Forexample, inert fillers, anti-irritants, tackifiers, excipients,fragrances, opacifiers, antioxidants, gelling agents, stabilizers,surfactant, emollients, coloring agents, preservatives, bufferingagents, other permeation enhancers, and other conventional components oftopical or transdermal delivery formulations as are known in the art.

The terms “enhancement,” “penetration enhancement” or “permeationenhancement” relate to an increase in the permeability of the skin,nail, hair, claw or hoof to a drug, so as to increase the rate at whichthe drug permeates through the skin, nail, hair, claw or hoof. Theenhanced permeation effected through the use of such enhancers can beobserved, for example, by measuring the rate of diffusion of the drugthrough animal skin, nail, hair, claw or hoof using a diffusion cellapparatus. A diffusion cell is described by Merritt et al. DiffusionApparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp.161-162. The term “permeation enhancer” or “penetration enhancer”intends an agent or a mixture of agents, which, alone or in combination,act to increase the permeability of the skin, nail, hair or hoof to adrug.

The term “excipients” is conventionally known to mean carriers, diluentsand/or vehicles used in formulating drug compositions effective for thedesired use.

The terms “effective amount” or a “therapeutically effective amount” ofa drug or pharmacologically active agent refers to a nontoxic butsufficient amount of the drug or agent to provide the desired effect. Inthe oral dosage forms of the present disclosure, an “effective amount”of one active of the combination is the amount of that active that iseffective to provide the desired effect when used in combination withthe other active of the combination. The amount that is “effective” willvary from subject to subject, depending on the age and general conditionof the individual, the particular active agent or agents, and theappropriate “effective” amount in any individual case may be determinedby one of ordinary skill in the art using routine experimentation.

The phrases “active ingredient”, “therapeutic agent”, “active”, or“active agent” mean a chemical entity which can be effective in treatinga targeted disorder, disease or condition.

The phrase “pharmaceutically acceptable” means moieties or compoundsthat are, within the scope of medical judgment, suitable for use inhumans without causing undesirable biological effects such as unduetoxicity, irritation, allergic response, and the like, for example.

The phrase “oral dosage form” means any pharmaceutical compositionadministered to a subject via the oral cavity, in which one or moreantiplatelet agents and one or more acid inhibitors are administeredconcurrently in combination, optionally with one or more additionaldrugs. Exemplary oral dosage forms include tablets, capsules, films,powders, sachets, granules, solutions, solids, suspensions or as morethan one distinct unit (e.g., granules, tablets, and/or capsulescontaining different actives) packaged together for co-administration,and other formulations known in the art. An oral dosage form can be one,two, three, four, five or six units. When the oral dosage form hasmultiple units, all of the units are contained within a single package,(e.g. a bottle or other form of packaging such as a blister pack). Whenthe oral dosage form is a single unit, it may or may not be in a singlepackage. In a preferred embodiment, the oral dosage form is one, two orthree units. In a particularly preferred embodiment, the oral dosageform is one unit.

The phrase “unit”, as used herein, refers to the number of discreteobjects to be administered which comprise the dosage form. In someembodiments, the dosage form includes a compound of the invention in onecapsule. This is a single unit. In some embodiments, the dosage formincludes a compound of the invention as part of a therapeuticallyeffective dosage of a cream or ointment. This is also a single unit. Insome embodiments, the dosage form includes a compound of the inventionand another active ingredient contained within one capsule, or as partof a therapeutically effective dosage of a cream or ointment or lotion.This is a single unit, whether or not the interior of the capsuleincludes multiple discrete granules of the active ingredient. In someembodiments, the dosage form includes a compound of the invention in onecapsule, and the active ingredient in a second capsule. This is a twounit dosage form, such as two capsules or tablets, and so such units arecontained in a single package. Thus the term ‘unit’ refers to the objectwhich is administered to the animal, not to the interior components ofthe object.

The term, “prodrug”, as defined herein, is a biologically inactivederivative of a parent drug molecule that exerts its pharmacologicaleffect only after chemical and/or enzymatic conversion to its activeform in vivo. Prodrugs include those designed to circumvent problemsassociated with delivery of the parent drug. This may be due to poorphysicochemical properties, such as poor chemical stability or lowaqueous solubility, and may also be due to poor pharmacokineticproperties, such as poor bioavailability or poor half-life. Thus,certain advantages of prodrugs may include improved chemical stability,absorption, and/or PK properties of the parent carboxylic acids.Prodrugs may also be used to make drugs more “patient friendly,” byminimizing the frequency (e.g., once daily) or route of dosing (e.g.,oral), or to improve the taste or odor if given orally, or to minimizepain if given parenterally.

In some embodiments, the prodrugs effect a “slow-release” of the activedrug, thereby changing the time-course of D-serine increase in a mannerthat improves the efficacy of the parent compound. For example,compounds of the invention that extend D-serine level increasesdemonstrate improved efficacy in animal models of cognition (e.g.,Contextual Fear Conditioning or Novel Object Recognition).

In some embodiments, the prodrugs are chemically more stable than theactive drug, thereby improving formulation and delivery of the parentdrug, compared to the drug alone.

Prodrugs for carboxylic acid analogs of the invention may include avariety of esters. In an exemplary embodiment, the pharmaceuticalcompositions of the invention include a carboxylic acid ester. In anexemplary embodiment, the prodrug is suitable for treatment/preventionof those diseases and conditions that require the drug molecule to crossthe blood brain barrier. In an exemplary embodiment, the prodrug entersthe brain, where it is converted into the active form of the drugmolecule. In one embodiment, a prodrug is used to enable an active drugmolecule to reach the inside of the eye after topical application of theprodrug to the eye. Additionally, a prodrug can be converted to itsparent compound by chemical or biochemical methods in an ex vivoenvironment. For example, a prodrug can be slowly converted to itsparent compound when placed in a transdermal patch reservoir with asuitable enzyme or chemical reagent.

The term “substrates” means pharmaceutically acceptable particulatematerials such as beads, particles, granules, pellets, and the like, inan oral dosage form.

The term, “substantially free”, as used herein, refers to a compositionwhich contains none of the substance or less than a therapeuticallyeffective amount of the substance for any known purpose for which thecomposition is intended.

The term “topical administration” refers to the application of apharmaceutical agent to the external surface of the skin, nail, hair,claw or hoof, such that the agent crosses the external surface of theskin, nail, hair, claw or hoof and enters the underlying tissues.Topical administration includes application of the composition to intactskin, nail, hair, claw or hoof, or to an broken, raw or open wound ofskin, nail, hair, claw or hoof. Topical administration of apharmaceutical agent can result in a limited distribution of the agentto the skin and surrounding tissues or, when the agent is removed fromthe treatment area by the bloodstream, can result in systemicdistribution of the agent.

The term “transdermal delivery” refers to the diffusion of an agentacross the barrier of the skin, nail, hair, claw or hoof resulting fromtopical administration or other application of a composition. Thestratum corneum acts as a barrier and few pharmaceutical agents are ableto penetrate intact skin. In contrast, the epidermis and dermis arepermeable to many solutes and absorption of drugs therefore occurs morereadily through skin, nail, hair, claw or hoof that is abraded orotherwise stripped of the stratum corneum to expose the epidermis.Transdermal delivery includes injection or other delivery through anyportion of the skin, nail, hair, claw or hoof or mucous membrane andabsorption or permeation through the remaining portion. Absorptionthrough intact skin, nail, hair, claw or hoof can be enhanced by placingthe active agent in an appropriate pharmaceutically acceptable vehiclebefore application to the skin, nail, hair, claw or hoof. Passivetopical administration may consist of applying the active agent directlyto the treatment site in combination with emollients or penetrationenhancers. As used herein, transdermal delivery is intended to includedelivery by permeation through or past the integument, i.e. skin, nail,hair, claw or hoof.

The term “substrates” means pharmaceutically acceptable particulatematerials such as beads, particles, granules, pellets, and the like, inan oral dosage form.

The term, “substantially free”, as used herein, refers to a compositionwhich contains none of the substance or less than a therapeuticallyeffective amount of the substance for any known purpose for which thecomposition is intended.

The term “microbial infection” refers to any infection of a host tissueby an infectious agent including, but not limited to, viruses, bacteria,mycobacteria, fungus and parasites (see, e.g., Harrison's Principles ofInternal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991);Williams et al., J. of Medicinal Chem. 42:1481-1485 (1999), herein eachincorporated by reference in their entirety).

“Biological medium,” as used herein refers to both in vitro and in vivobiological milieus. Exemplary in vitro “biological media” include, butare not limited to, cell culture, tissue culture, homogenates, plasmaand blood. In vivo applications are generally performed in mammals,preferably humans.

A “human nail unit”, as defined herein, can be the nail plate, the nailbed, proximal nail fold, lateral nail fold and combinations thereof.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include triflate, chloro, bromoand iodo groups; sulfonic ester groups, such as mesylate, tosylate,brosylate, nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The term “amino-protecting group” means a protecting group suitable forpreventing undesired reactions at an amino nitrogen. Representativeamino-protecting groups include, but are not limited to, formyl; acylgroups, for example alkanoyl groups, such as acetyl, trichloroacetyl ortrifluoroacetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl(Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl(Bn), trityl (Tr), and 1,1-di-(4′-methoxyphenyl)methyl; silyl groups,such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and thelike.

The term “hydroxy-protecting group” means a protecting group suitablefor preventing undesired reactions at a hydroxy group. Representativehydroxy-protecting groups include, but are not limited to, alkyl groups,such as methyl, ethyl, and tert-butyl; acyl groups, for example alkanoylgroups, such as acetyl; arylmethyl groups, such as benzyl (Bn),p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl(benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) andtert-butyldimethylsilyl (TBS); and the like.

Boron is able to form dative bonds (or coordination bonds) with oxygen,sulfur or nitrogen under some circumstances in this invention. Dativebonds are usually weaker than covalent bonds. In situations where aboron atom is covalently bonded to at least one oxygen, sulfur ornitrogen, and is at the same time datively bonded to an oxygen, sulfuror nitrogen, respectively, the dative bond and covalent bond between theboron and the two identical heteroatoms can interconvert or be in theform of a resonance hybrid. There is potential uncertainty surroundingthe exact nature and extent of electron sharing in these situations. Thestructures supplied are not intended to include any and all possiblebonding scenarios between boron and the atom to which it is bound. Nonlimiting examples of these bonds are as follows:

“Salt counterion”, as used herein, refers to positively charged ionsthat associate with a compound of the invention when the boron is fullynegatively or partially negatively charged. Examples of salt counterionsinclude H⁺, H₃O⁺, ammonium, potassium, calcium, magnesium and sodium.

The compounds comprising a boron bonded to a carbon and threeheteroatoms (such as three oxygens described in this section) canoptionally contain a fully negatively charged boron or partiallynegatively charged boron, due to the nature of the dative bond betweenthe boron and one of the oxygens. Due to the negative charge, apositively charged counterion may associate with this compound, thusforming a salt. Examples of positively charged counterions include H⁺,H₃O⁺, calcium, sodium, ammonium, potassium. The salts of these compoundsare implicitly contained in descriptions of these compounds.

The present invention also encompasses compounds that are poly- ormulti-valent species, including, for example, species such as dimers,trimers, tetramers and higher homologs of the compounds of use in theinvention or reactive analogues thereof. For example, dimers ofoxaboroles can form under the following conditions:

The present invention also encompasses compounds that are anhydrides ofthe cyclic boronic esters are synthesized by subjecting these compoundsto dehydrating conditions. Examples of these anhydrides are providedbelow:

Trimers of the compounds of the invention are also produced. Forexample, trimers of acyclic boronic esters can be formed as follows:

Polymers of the compounds of the invention are also produced through theremoval of certain protecting groups in strong acid. For example,trimers of acyclic boronic esters can be formed as follows:

Also of use in the present invention are compounds that are poly- ormulti-valent species, including, for example, species such as dimers,trimers, tetramers and higher homologs of the compounds of use in theinvention or reactive analogues thereof. The poly- and multi-valentspecies can be assembled from a single species or more than one speciesof the invention. For example, a dimeric construct can be “homo-dimeric”or “heterodimeric.” Moreover, poly- and multi-valent constructs in whicha compound of the invention or a reactive analogue thereof, is attachedto an oligomeric or polymeric framework (e.g., polylysine, dextran,hydroxyethyl starch and the like) are within the scope of the presentinvention. The framework is preferably polyfunctional (i.e. having anarray of reactive sites for attaching compounds of use in theinvention). Moreover, the framework can be derivatized with a singlespecies of the invention or more than one species of the invention.

Moreover, the present invention includes the use of compounds within themotif set forth in the formulae contained herein, which arefunctionalized to afford compounds having water-solubility that isenhanced relative to analogous compounds that are not similarlyfunctionalized. Thus, any of the substituents set forth herein can bereplaced with analogous radicals that have enhanced water solubility.For example, it is within the scope of the invention to replace ahydroxyl group with a diol, or an amine with a quaternary amine, hydroxyamine or similar more water-soluble moiety. In a preferred embodiment,additional water solubility is imparted by substitution at a site notessential for the activity towards the editing domain of the compoundsset forth herein with a moiety that enhances the water solubility of theparent compounds. Methods of enhancing the water-solubility of organiccompounds are known in the art. Such methods include, but are notlimited to, functionalizing an organic nucleus with a permanentlycharged moiety, e.g., quaternary ammonium, or a group that is charged ata physiologically relevant pH, e.g. carboxylic acid, amine. Othermethods include, appending to the organic nucleus hydroxyl- oramine-containing groups, e.g. alcohols, polyols, polyethers, and thelike. Representative examples include, but are not limited to,polylysine, polyethyleneimine, poly(ethyleneglycol) andpoly(propyleneglycol). Suitable functionalization chemistries andstrategies for these compounds are known in the art. See, for example,Dunn, R. L., et al., Eds. POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS, ACSSymposium Series Vol. 469, American Chemical Society, Washington, D.C.1991.

II. Introduction

The present invention has multiple aspects. These aspects includeinventions directed to compounds, pharmaceutical formulations, methodsof treating a condition, enhancing an effect, increasing the productionof a cytokine and/or chemokine, decreasing the production of a cytokineand/or chemokine, increasing the release of a cytokine and/or chemokine,decreasing the release of a cytokine and/or chemokine, or inhibiting aphosphodiesterase.

III. Compounds IIIa.

In a first aspect, the invention is a compound of the invention. In anexemplary embodiment, the invention is a compound described herein. Inan exemplary embodiment, the compound is according to a formuladescribed herein. In an exemplary embodiment, the compound is a memberselected from D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12, D13, D14,D15, D16, D17, D18, D19, D20, D21, D22, D23, D24, D25, D26, D27, D28,D29, D30, D31, D32, D33, D34, D35, D36, D37, D38, D39, D40, D41, D42,D43, D44, D45, D46, D47, D48, D49, D50, D51, D52, D53, D54, D55, D56,D57, D58, D59, D60, D61, D62, D63, D64, D65, D66, D67, D68, D69, D70,D71, D72, D73, D74, D75, D76, D77, D78, D79, D80, D81, D83, D84, D85,D86, D87, D88, D89, D90, D91, D92, D93, D94, D95, D96, D97, D98, D99,D100, D101, D102, D103, D104, D105, D106, D107, D108, D109, D110, D111,D112, D113, D114, D115, D116, D117, D118, D119, D120, D121, D122, D123,D124, D125, D126, D127, D128, D129, D130, D131, D132, D133, D134, D135,D136, D137, D138, D139, D140, D141, D142, D143, D144, D145, D146, D147,D148, D149, D150, D151, D152, D153, D154, D155, D156, D157, D158, D159,D160, D161, D162, D163, D164, D165, D166, D167, D168, D169, D170, D171,D172, D173, D174, D175, D176, D177, D178, D179, D180, D181, D182, D183,D184, D185, D186, D187, D188, D189, D190, D191, D192, D193, D194, D195,D196, D197, D198, D199, D200, D201, D202, D203, D204, D205, D206, D207,D208, D209, D210, D211, D212, D213, D214, D215, D216, D217, D218, D219,D220, D221, D222, D223, D224, D225, D228 and D229. In an exemplaryembodiment, the compound is a member selected from

In a second aspect, the invention provides a compound having a structureaccording to the formula:

wherein R* is a member selected from H, a negative charge and apositively charged counterion. X is a member selected from CR^(a),CR^(b) and N. R^(a) is a member selected from CN, —C(O)NR¹R², and—C(O)OR³. R^(b) and R^(c) are members independently selected from H,OR⁴, NR⁴R⁵, SR⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)₂NR⁴R⁵, —C(O)R⁴, —C(O)OR⁴,—C(O)NR⁴R⁵, nitro, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl,wherein each R¹, R², R⁴ and R⁵ are members independently selected fromH, nitro, halogen, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl. R³is a member selected from H and substituted or unsubstituted alkyl.There is a proviso that R¹ and R², together with the atoms to which theyare attached, are optionally combined to form a 5- to 7-memberedsubstituted or unsubstituted heterocycloalkyl ring. There is a provisothat R⁴ and R⁵, together with the atoms to which they are attached, areoptionally combined to form a 5- to 7-membered substituted orunsubstituted heterocycloalkyl ring. There is a proviso R^(b) and R^(c)cannot both be H. There is a proviso that R^(a) and R^(b) are optionallyjoined to form a 5- to 8-membered ring comprising two oxo moieties.

In an exemplary embodiment, X is N. In an exemplary embodiment, X is CH.In an exemplary embodiment, X is CR^(b).

In an exemplary embodiment, R* is H.

In an exemplary embodiment, at least one of R^(b) and R^(c) is a memberselected from F and Cl. In an exemplary embodiment, at least one ofR^(b) and R^(c) is substituted or unsubstituted alkyl, which is a memberselected from unsubstituted alkyl, hydroxyalkyl, haloalkyl,trihaloalkyl, substituted or unsubstituted aminoalkyl, —CH₂C(O)OR⁶,—CH₂NHC(O)R⁶, —CH₂NR⁶R⁷, wherein each R⁶ and R⁷ are membersindependently selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl and substituted or unsubstitutedheteroaryl, with the proviso that R⁶ and R⁷, together with the atoms towhich they are attached, are optionally combined to form a 5- to7-membered substituted or unsubstituted heterocycloalkyl ring.

In an exemplary embodiment, R^(b) is H. In an exemplary embodiment,R^(c) is H. In an exemplary embodiment, R^(c) is H, and R^(b) is amember selected from halogen, unsubstituted alkyl, halogen substitutedalkyl, unsubstituted alkoxy. In an exemplary embodiment, R^(c) is H, andR^(b) is a member selected from methyl and ethyl. In an exemplaryembodiment, R^(c) is H, and R^(b) is a member selected fromunsubstituted C₃ alkyl, unsubstituted C₄ alkyl, unsubstituted C₅ alkyland unsubstituted C₆ alkyl. In an exemplary embodiment, R^(b) is H, andR^(c) is trifluoromethyl. In an exemplary embodiment, R^(c) is H, andR^(b) is a member selected from methoxy, ethoxy, unsubstituted C₃alkoxy, unsubstituted C₄ alkoxy, unsubstituted C₅ alkoxy andunsubstituted C₆ alkoxy.

In an exemplary embodiment, at least one of R^(b) and R^(c) is a memberselected from —CH₂C(O)OR⁶, —CH₂NHC(O)R⁶, —CH₂NR⁶R⁷, wherein each R⁶ andR⁷ are members independently selected from H, methyl, trifluoromethyl,ethyl, propyl, butyl, t-butyl, —C(O)H, wherein R⁶ and R⁷, together withthe together with nitrogen to which they are attached, are optionallycombined to form a member selected from 4-methylpiperazinyl,piperidinyl, morpholino and pyrrolidinyl.

In an exemplary embodiment, at least one of R^(b) and R^(c) is methyl,trifluoromethyl, —CH₂OH, —CH₂N(CH₃)₂,

In an exemplary embodiment, at least one of R^(b) and R^(c) is a memberselected from —OR⁴, —C(O)R⁴, —C(O)OR⁴ and —C(O)NR⁴R⁵, wherein each R⁴and R⁵ are members independently selected from H, methyl, ethyl,methoxyethyl, cyclopropyl, —CH₂C(O)OR⁸, —CH₂C(O)NR⁸R⁹,2-(dimethylamino)ethyl, 2-pyridinylmethyl, 2-(4-cyano)pyridinyl, withthe proviso that R⁸ and R⁹, together with the atoms to which they areattached, are optionally combined to form a 5- to 7-membered substitutedor unsubstituted heterocycloalkyl ring.

In an exemplary embodiment, at least one of R^(b) and R^(c) is a memberselected from —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂C(O)OH,—OCH₂C(O)OCH₂CH₃, —OCH₂C(O)OC(CH₃)₃, —C(O)OCH₃, —C(O)OH, —C(O)H,—OCH₂C(O)N(CH₂CH₃)₂,

In an exemplary embodiment, at least one of R^(b) and R^(c) is a memberselected from F, Cl, methyl, trifluoromethyl, —CH₂OH, —CH₂N(CH₃)₂, —OH,—OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂C(O)OH, —OCH₂C(O)OCH₂CH₃,—OCH₂C(O)OC(CH₃)₃, —C(O)OCH₃, —C(O)OH, —C(O)H, —OCH₂C(O)N(CH₂CH₃)₂,

In an exemplary embodiment, the compound has a structure according tothe formula

wherein X, R*, R^(b) and R^(c) are as described herein.

In an exemplary embodiment, at least one of R^(b) and R^(c) is a memberselected from halogen, haloalkyl, —C(O)R⁴, —C(O)OR⁴, —C(O)NR⁴R⁵,—CH₂C(O)OR⁴, —CH₂NHC(O)R⁴ and OR⁴, wherein R⁴ and R⁵ are membersindependently selected from H and substituted or unsubstituted alkyl

In an exemplary embodiment, at least one of R^(b) and R^(c) is a memberselected from F, Cl, methyl, trifluoromethyl, —CH₂OH, —CH₂N(CH₃)₂, —OH,—OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂C(O)OH, —OCH₂C(O)OCH₂CH₃,—OCH₂C(O)OC(CH₃)₃, —C(O)OCH₃, —C(O)OH, —C(O)H, —OCH₂C(O)N(CH₂CH₃)₂,

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein X, R*, R^(b) and R^(c) are as described herein.

In an exemplary embodiment, at least one of R^(b) and R^(c) is a memberselected from F, Cl, methyl, trifluoromethyl, —CH₂OH, —CH₂N(CH₃)₂, —OH,—OCH₃, —OCH₂CH₃, —OCH₂C(O)OH, —OCH₂CH₂OCH₃, —OCH₂C(O)OCH₂CH₃,—OCH₂C(O)OC(CH₃)₃, —C(O)OCH₃, —C(O)OH, —C(O)H, —OCH₂C(O)N(CH₂CH₃)₂,

In an exemplary embodiment, R^(c) is H, and R^(b) is a member selectedfrom F, Cl, methyl, trifluoromethyl, —CH₂OH, —CH₂N(CH₃)₂, —OH, —OCH₃,—OCH₂CH₃, —OCH₂C(O)OH, —OCH₂CH₂OCH₃, —OCH₂C(O)OCH₂CH₃,—OCH₂C(O)OC(CH₃)₃, —C(O)OCH₃, —C(O)OH, —C(O)H, —OCH₂C(O)N(CH₂CH₃)₂,

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein X is N or CH or CR^(b), R^(b) is a member selected from halogenand substituted or unsubstituted alkyl, C(O)R⁴, C(O)OR⁴, OR⁴, NR⁴R⁵,wherein R⁴ and R⁵ are members independently selected from H, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, with the proviso that R⁴ and R⁵, together withthe atoms to which they are attached, are optionally combined to form a5- to 7-membered substituted or unsubstituted heterocycloalkyl ring, andsalts thereof. In an exemplary embodiment, R^(b) is a member selectedfrom OR⁴ and NR⁴R⁵, wherein R⁴ and R⁵ are members independently selectedfrom H, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl, with the proviso that R⁴ andR⁵, together with the atoms to which they are attached, are optionallycombined to form a 5- to 7-membered substituted or unsubstitutedheterocycloalkyl ring.

In an exemplary embodiment, R^(b) is alkyl, optionally substituted witha member selected from halogen, OR^(4a), C(O)OR^(4a), NR^(4a)R^(4b),substituted or unsubstituted heterocycloalkyl or unsubstitutedheteroaryl, wherein R^(4a) and R^(4b) are independently selected from H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. In an exemplary embodiment,R^(4a) is H or unsubstituted alkyl. In an exemplary embodiment, R^(4b)is H or unsubstituted alkyl or C(O)H. In an exemplary embodiment, R^(b)is fluoro. In an exemplary embodiment, R^(b) is chloro.

In an exemplary embodiment, R^(b) is OH. In an exemplary embodiment,R^(b) is OR⁴, wherein R⁴ is alkyl is optionally substituted with atleast one halogen, hydroxyl, ether, carboxy or ester moiety.

In an exemplary embodiment, R^(b) is OR⁴, wherein R⁴ is unsubstitutedalkyl. In an exemplary embodiment, R^(b) is OR⁴, wherein R⁴ isunsubstituted C₁ or C₂ or C₃ alkyl. In an exemplary embodiment, R^(b) isOR⁴, wherein R⁴ is unsubstituted C₄ or C₅ or C₆ alkyl. In an exemplaryembodiment, R^(b) is OR⁴, wherein R⁴ is methyl or ethyl or propyl orisopropyl or isobutyl.

In an exemplary embodiment, R^(b) is OR⁴, wherein R⁴ is alkylsubstituted with at least one halogen. In an exemplary embodiment, R^(b)is OR⁴, wherein R⁴ is alkyl substituted with one or two or threehalogen(s). In an exemplary embodiment, R^(b) is O(CH₂)_(m1)R³¹, whereinm1 is 1 or 2 or 3 or 4 or 5 or 6 and R³¹ is a methyl moiety wherein atleast one of the methyl hydrogens is substituted with a halogen. In anexemplary embodiment, the halogen is chloro. In an exemplary embodiment,the halogen is fluoro. In an exemplary embodiment, R³¹ is —CF₃. In anexemplary embodiment, R³¹ is —CHF₂. In an exemplary embodiment, m1 is 1or 2 or 3. In an exemplary embodiment, R^(b) is —OCH₂CF₃. In anexemplary embodiment, R^(b) is —OCH₂CHF₂.

In an exemplary embodiment, R^(b) is —O(CH₂)_(m1)OC(O)R^(4d), wherein m1is a number selected from 1 or 2 or 3 or 4 or 5 or 6 and R^(4d) isunsubstituted alkyl. In an exemplary embodiment, m1 is 1 or 2 or 3. Inan exemplary embodiment, m1 is 2. In an exemplary embodiment, R^(4d) isunsubstituted C₁ or C₂ or C₃ alkyl. In an exemplary embodiment, R^(4d)is unsubstituted C₄ or C₅ or C₆ alkyl. In an exemplary embodiment,R^(4d) is methyl. In an exemplary embodiment, R^(b) is —O(CH₂)₂OC(O)CH₃.

In an exemplary embodiment, R^(b) is —O(CH₂)_(m1)C(O)R^(4d), wherein m1is a number selected from 1 or 2 or 3 or 4 or 5 or 6 and R^(4d) isunsubstituted alkyl. In an exemplary embodiment, m1 is 2 or 3 or 4. Inan exemplary embodiment, m1 is 3. In an exemplary embodiment, R^(4d) isunsubstituted C₁ or C₂ or C₃ alkyl. In an exemplary embodiment, R^(4d)is unsubstituted C₄ or C₅ or C₆ alkyl. In an exemplary embodiment,R^(4d) is methyl. In an exemplary embodiment, R^(b) is —O(CH₂)₃C(O)CH₃.

In an exemplary embodiment, R^(b) is —O(CH₂)_(m1)C(O)OR^(4d), wherein m1is a number selected from 1 or 2 or 3 or 4 or 5 or 6 and R^(4d) is H orunsubstituted alkyl. In an exemplary embodiment, R^(b) is—OCH₂C(O)OR^(4d), wherein R^(4d) is as described herein. In an exemplaryembodiment, R^(4d) is H or methyl or ethyl or t-butyl. In an exemplaryembodiment, R^(b) is —O(CH₂)C(O)OCH₂CH₃ or —O(CH₂)C(O)OH or—O(CH₂)C(O)OC(CH₃)₃.

In an exemplary embodiment, R^(b) is OR⁴, wherein R⁴ is alkylsubstituted with a substituted or unsubstituted amino. In an exemplaryembodiment, R^(b) is —O(CH₂)_(m2)C(O)NR^(4e)R^(4f), wherein m2 is anumber selected from 1 or 2 or 3 or 4 or 5 or 6, and R^(4e) and R^(4f)are independently selected from H or unsubstituted alkyl, or R^(4e) andR^(4f), together with the nitrogen to which they are attached, areoptionally joined to form a substituted or unsubstituted 4 to 8 memberedring.

In an exemplary embodiment, R^(b) is —OCH₂C(O)NR^(4e)R^(4f), whereinR^(4e) and R^(4f) are as described herein. In an exemplary embodiment,R^(4e) and R^(4f) are the same and are independently selectedunsubstituted alkyl. In an exemplary embodiment, R^(4e) and R^(4f) aredifferent and are independently selected unsubstituted alkyl. In anexemplary embodiment, R^(4e) is H. In an exemplary embodiment, R^(4f) isH. In an exemplary embodiment, R^(4e) and R^(4f) are ethyl. In anexemplary embodiment, R^(4e) and R^(4f), together with the nitrogen towhich they are attached, are joined to form piperazinyl, eitherunsubstituted or substituted with unsubstituted alkyl on the nitrogen atthe 4-position. In an exemplary embodiment, R^(4e) and R^(4f), togetherwith the nitrogen to which they are attached, are joined to formN-methyl piperazinyl. In an exemplary embodiment, R^(4e) and R^(4f),together with the nitrogen to which they are attached, are joined toform piperidinyl, either unsubstituted or substituted with unsubstitutedalkyl. In an exemplary embodiment, R^(4e) and R^(4f), together with thenitrogen to which they are attached, are joined to form 4-methylpiperidinyl. In an exemplary embodiment, R^(4e) and R^(4f), togetherwith the nitrogen to which they are attached, are joined to formunsubstituted morpholinyl.

In an exemplary embodiment, R^(b) is OR⁴, wherein R⁴ is unsubstitutedalkyl. In an exemplary embodiment, R⁴ is C₁ or C₂ or C₃ or C₄ or C₅ orC₆ alkyl. In an exemplary embodiment, R⁴ is C₁ alkyl. In an exemplaryembodiment, R^(b) is OR⁴, wherein R⁴ is alkyl substituted withunsubstituted pyridinyl. In an exemplary embodiment, R^(b) is

wherein m3 is 1 or 2 or 3 or 4 or 5 or 6. In an exemplary embodiment, m3is 1.

In an exemplary embodiment, R^(b) is OR⁴, wherein R⁴ is substituted orunsubstituted cycloalkyl. In an exemplary embodiment, R^(b) is OR⁴,wherein R⁴ is unsubstituted cycloalkyl. In an exemplary embodiment,R^(b) is OR⁴, wherein R⁴ is cyclopenyl. In an exemplary embodiment, R⁴is unsubstituted cyclohexyl.

In an exemplary embodiment, R^(b) is OR⁴, wherein R⁴ is alkylsubstituted with unsubstituted alkoxy. In an exemplary embodiment, R^(b)is —O(CH₂)_(m5)OR³⁰, wherein m5 is 1 or 2 or 3 or 4 or 5 or 6 and R³⁰ isH or unsubstituted alkyl or unsubstituted tetrahydropyran. In anexemplary embodiment, R³⁰ is C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. Inan exemplary embodiment, m5 is 1 or 2 or 3. In an exemplary embodiment,m5 is 2. In an exemplary embodiment, R³⁰ is C₁ or C₂ or C₃ alkyl. In anexemplary embodiment, R³⁰ is C₄ or C₅ or C₆ alkyl. In an exemplaryembodiment, R³⁰ is H. In an exemplary embodiment, R³⁰ is methyl orisopropyl. In an exemplary embodiment, R³⁰ is 2-tetrahydropyran. In anexemplary embodiment, R^(b) is —O(CH₂)₂OC(CH₃)₂ or —O(CH₂)₂OH or—O(CH₂)₂O-THP (TetraHydroPyran).

In an exemplary embodiment, R^(b) is OR⁴, wherein R⁴ is alkylsubstituted with unsubstituted cycloalkyl. In an exemplary embodiment,R^(b) is —O(CH₂)_(m5)OR³⁰, wherein m5 is 1 or 2 or 3 or 4 or 5 or 6 andR³⁰ is a 3-8 membered cycloalkyl. In an exemplary embodiment, R³⁰ is a3-6 membered cycloalkyl. In an exemplary embodiment, R³⁰ is a memberselected from cyclopropyl and cyclopentyl. In an exemplary embodiment,m5 is 1 or 2 or 3. In an exemplary embodiment, m5 is 1.

In an exemplary embodiment, R^(b) is C(O)R⁴, wherein R⁴ is unsubstitutedalkyl. In an exemplary embodiment, R⁴ is C₁ or C₂ or C₃ or C₄ or C₅ orC₆ alkyl. In an exemplary embodiment, R⁴ is C₁ alkyl. In an exemplaryembodiment, R^(b) is C(O)H. In an exemplary embodiment, R^(b) is C₁ orC₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, R^(b) isC₁ alkyl. In an exemplary embodiment, R^(b) is alkyl substituted withhalogen. In an exemplary embodiment, R^(b) is alkyl substituted with atleast one halogen. In an exemplary embodiment, R^(b) is alkylsubstituted with at least one fluoro. In an exemplary embodiment, R^(b)is CF₃.

In an exemplary embodiment, R^(b) is alkyl substituted with hydroxy. Inan exemplary embodiment, R^(b) is —(CH₂)_(m4)OH, wherein m4 is a numberselected from 1 or 2 or 3 or 4 or 5 or 6. In an exemplary embodiment, m4is 1.

In an exemplary embodiment, R^(b) is alkyl substituted with carboxy orester. In an exemplary embodiment, R^(b) is —(CH₂)_(m1)C(O)OR⁴, whereinm1 is a number selected from 1 or 2 or 3 or 4 or 5 or 6 and R^(4a) is Hor unsubstituted alkyl.

In an exemplary embodiment, R^(b) is —CH₂C(O)OR^(4a), wherein R^(4a) isas described herein. In an exemplary embodiment, R^(4a) is H or methylor ethyl or t-butyl.

In an exemplary embodiment, R^(b) is alkyl substituted with amino. In anexemplary embodiment, R^(b) is —(CH₂)_(m7)NR^(4a)R^(4b), wherein m7 is anumber selected from 1 or 2 or 3 or 4 or 5 or 6 and R^(4a) and R^(4b)are members independently selected from H and unsubstituted alkyl andformyl, or R^(4a) and R^(4b), together with the nitrogen to which theyare attached, are optionally joined to form a substituted orunsubstituted 4 to 8 membered ring. In an exemplary embodiment, R^(4b)is as described herein, R^(4a) is H. In an exemplary embodiment, R^(4a)is as described herein, R^(4b) is H. In an exemplary embodiment, R^(4b)is as described herein, R^(4a) is methyl. In an exemplary embodiment,R^(4a) is as described herein, R^(4b) is methyl. In an exemplaryembodiment, m7 is 1. In an exemplary embodiment, R^(4a) and R^(4b),together with the nitrogen to which they are attached, are joined toform piperazinyl, either unsubstituted or substituted with unsubstitutedalkyl on the nitrogen at the 4-position. In an exemplary embodiment,R^(4a) and R^(4b), together with the nitrogen to which they areattached, are joined to form N-methyl piperazinyl. In an exemplaryembodiment, R^(4a) and R^(4b), together with the nitrogen to which theyare attached, are joined to form piperidinyl, either unsubstituted orsubstituted with unsubstituted alkyl. In an exemplary embodiment, R^(4a)and R^(4b), together with the nitrogen to which they are attached, arejoined to form 4-methyl piperidinyl. In an exemplary embodiment, R^(4a)and R^(4b), together with the nitrogen to which they are attached, arejoined to form unsubstituted morpholinyl.

In an exemplary embodiment, R^(b) is NH₂. In an exemplary embodiment,R^(b) is NR⁴R⁵ wherein R⁴ is a member selected from H and unsubstitutedalkyl, and R⁵ is a member selected from substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. In an exemplary embodiment, R^(b) is NR⁴R⁵, R⁴ is asdescribed herein, R⁵ is unsubstituted alkyl. In an exemplary embodiment,R^(b) is NR⁴R⁵, wherein R⁴ is H, R⁵ is as described herein. In anexemplary embodiment, R^(b) is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl,R⁵ is as described herein. In an exemplary embodiment, R^(b) is NR⁴R⁵,wherein R⁵ is as described herein, R⁴ is unsubstituted C₁ or C₂ or C₃ orC₄ or C₅ or C₆ alkyl. In an exemplary embodiment, R^(b) is NR⁴R⁵,wherein R⁴ is unsubstituted C₁ or C₂ or C₃ alkyl and R⁵ is as describedherein. In an exemplary embodiment, R^(b) is NR⁴R⁵, wherein R⁴ is methyland R⁵ is as described herein. In an exemplary embodiment, R^(b) isNR⁴R⁵, wherein R⁴ is as described herein R⁵ is unsubstituted C₁ or C₂ orC₃ or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, R^(b) is NR⁴R⁵,wherein R⁵ is a member selected from methyl and tert-butyl, and R⁴ is asdescribed herein.

In an exemplary embodiment, R^(b) is NR⁴R⁵, wherein R⁴ is as describedherein, R⁵ is alkyl, substituted with a member selected from OH,unsubstituted arylalkoxy, unsubstituted alkoxy, and unsubstituted aryl.In an exemplary embodiment, R^(b) is NR⁴R⁵, wherein R⁵ is —(CH₂)_(m8)Ph.

In an exemplary embodiment, R^(b) is NR⁴R⁵, wherein R⁵ is—(CH₂)_(m8)OR²⁶, wherein m8 is a number selected from 1 or 2 or 3 or 4or 5 or 6 and R²⁶ is a member selected from H, unsubstituted or arylsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplaryembodiment, m8 is 1 or 2 or 3. In an exemplary embodiment, m8 is 2. Inan exemplary embodiment, R²⁶ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅or C₆ alkyl. In an exemplary embodiment, R²⁶ is methyl. In an exemplaryembodiment, R²⁶ is benzyl. In an exemplary embodiment, R^(b) is NR⁴R⁵,wherein R⁴ is as described herein, R⁵ is —(CH₂)_(m8)O(CH₂)_(m9)Ph,wherein m8 and m9 are each independently selected from 1 or 2 or 3 or 4or 5 or 6. In an exemplary embodiment, R^(b) is NR⁴R⁵, wherein R⁴ is asdescribed herein R⁵ is —(CH₂)_(m8)O(CH₂)_(m9)Ph, wherein m8 and m9 areeach independently selected from 1 or 2 or 3. In an exemplaryembodiment, R^(b) is NR⁴R⁵, wherein R⁴ is as described herein, R⁵ is—(CH₂)_(m8)O(CH₂)Ph. In an exemplary embodiment, R^(b) is NR⁴R⁵, whereinR⁴ is as described herein R⁵ is —(CH₂)₂O(CH₂)_(m9)Ph. In an exemplaryembodiment, R^(b) is NR⁴R⁵, wherein R⁴ is as described herein R⁵ is—(CH₂)₂O(CH₂)Ph.

In an exemplary embodiment, R^(b) is a member selected from —NH(CH₂)₂OH,—NH(CH₂)₂OCH₃, —NHCH₃, —NHC(CH₃)₃, —NH(CH₂)Ph, —NH(CH₂)₂O(CH₂)Ph.

In an exemplary embodiment, R^(b) is a member selected from —N(CH₃)₂,—N(CH₃)(CH₂)₂OH, —N(CH₃)(CH₂)₂OCH₃, —NHCH₃, —NHC(CH₃)₃, —NH(CH₂)Ph,—NH(CH₂)₂O(CH₂)Ph.

In an exemplary embodiment, R^(b) is —NR⁴R⁵, wherein R⁴ and R⁵, togetherwith the nitrogen to which they are attached, are joined to form asubstituted or unsubstituted 4 to 8 membered ring. In an exemplaryembodiment, the only non-carbon atom which forms the ring is thenitrogen to which R⁴ and R⁵ are attached. In an exemplary embodiment,R^(b) is —NR⁴R⁵, wherein R⁴ and R⁵, together with the nitrogen to whichthey are attached, are joined to form a member selected from substitutedor unsubstituted pyrrolidinyl and substituted or unsubstitutedpiperidinyl. In an exemplary embodiment, R^(b) is —NR⁴R⁵, wherein R⁴ andR⁵, together with the nitrogen to which they are attached, are joined toform a member selected from unsubstituted pyrrolidinyl and unsubstitutedpiperidinyl. In an exemplary embodiment, the only non-carbon atom whichforms the ring is nitrogen. In an exemplary embodiment, the ringcontains one nitrogen atom and one oxygen atom. In an exemplaryembodiment, the ring contains one nitrogen atom and one oxygen atom. Inan exemplary embodiment, R^(b) is —NR⁴R⁵, wherein R⁴ and R⁵, togetherwith the nitrogen to which they are attached, are joined to formsubstituted or unsubstituted morpholinyl. In an exemplary embodiment,R^(b) is —NR⁴R⁵, wherein R⁴ and R⁵, together with the nitrogen to whichthey are attached, are joined to form unsubstituted morpholinyl.

In an exemplary embodiment, the compound has a structure according tothe following formula:

and salts thereof, wherein R^(b) is as described herein.

In an exemplary embodiment, the compound has a structure according tothe following formula:

and salts thereof, wherein R^(b) is as described herein.

In an exemplary embodiment, the compound has a structure according tothe following formula:

and salts thereof, wherein R^(b) is as described herein.

In an exemplary embodiment, the compound has a structure according tothe following formula:

and salts thereof, wherein R^(b) is as described herein.

In an exemplary embodiment, the compound has a structure according tothe following formula:

and salts thereof, wherein R^(b) is as described herein.

In an exemplary embodiment, the compound has a structure according tothe following formula:

and salts thereof, wherein R^(b) is as described herein.

In an exemplary embodiment, the compound has a structure according tothe following formula:

and salts thereof, wherein R^(b) is as described herein.

In an exemplary embodiment, the compound has a structure according tothe following formula:

and salts thereof, wherein R^(b) is as described herein.

In an exemplary embodiment, the compound is a member selected from D46,D86, D99, D100, D107, D108, D114, D122, D125, D126, D127, D128, D131,D140 and D141, and salts thereof. In an exemplary embodiment, thecompound is a member selected from D95, D96, D97, D102, D110, D111,D113, D115, D121, D129, D130, D132, and salts thereof. In an exemplaryembodiment, the compound is a member selected from D47, D109, D116,D118, D119, D120, D123, and salts thereof. In an exemplary embodiment,the compound is a member selected from D98, D101, D106, and saltsthereof. In an exemplary embodiment, the compound is a member selectedfrom D11, D12, D37, D38, D39, D40, D41, D42, D43, D124, D142, D143,D146, and salts thereof. In an exemplary embodiment, the compound is amember selected from D14, D15, D16, D17, D28, D29, D30, D31, D133, D134,D135, D144, D145, D147, and salts thereof.

In an exemplary embodiment, the compound has a structure which is amember selected from

wherein R* is as defined herein.

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R³, X, R*, R^(b) and R^(c) are as described herein.

In an exemplary embodiment, R³ is H. In an exemplary embodiment, R³ isunsubstituted alkyl. In an exemplary embodiment, R³ is methyl. In anexemplary embodiment, R³ is C₂ alkyl. In an exemplary embodiment, R³ isC₃ alkyl. In an exemplary embodiment, R³ is C₄ alkyl. In an exemplaryembodiment, R³ is C₅ alkyl. In an exemplary embodiment, R³ is C₆ alkyl.

In an exemplary embodiment, at least one of R^(b) and R^(c) is a memberselected from —C(O)NR⁴R⁵, —C(O)OR⁴, —CH₂C(O)OR⁴, —CH₂NHC(O)R⁴ and OR⁴,wherein each R⁴ and R⁵ is a member independently selected from H,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, at least one of R^(b) and R^(c) is a memberselected from F, Cl, methyl, trifluoromethyl, —CH₂OH, —CH₂N(CH₃)₂, —OH,—OCH₃, —OCH₂CH₃, —OCH₂C(O)OH, —OCH₂C(O)OCH₂CH₃, —OCH₂C(O)OC(CH₃)₃,—C(O)OCH₃, —C(O)OH, —C(O)H, —OCH₂C(O)N(CH₂CH₃)₂,

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R³, X, R*, R^(b) and R^(c) are as described herein.

In an exemplary embodiment, at least one of R^(b) and R^(c) is a memberselected from —C(O)NH₂, —OH, —OCH₃, cyclopropyloxy and4-cyanopyridin-2-yloxy.

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R³, X, R* are as described herein, and at least one of R^(b) andR^(c) is a member selected from F, Cl, methyl, trifluoromethyl, —CH₂OH,—CH₂N(CH₃)₂, —OH, —OCH₃, —OCH₂CH₃, —OCH₂C(O)OH, —OCH₂C(O)OCH₂CH₃,—OCH₂C(O)OC(CH₃)₃, —C(O)OCH₃, —C(O)OH, —C(O)H, —OCH₂C(O)N(CH₂CH₃)₂,

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R³, X and R* are as described herein, and at least one of R^(b)and R^(c) is a member selected from —C(O)NR⁴R⁵, —C(O)OR⁴, —CH₂C(O)OR⁴,—CH₂NHC(O)R⁴ and OR⁴, wherein each R⁴ and R⁵ is a member independentlyselected from H, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound has a formula which is a memberselected from

wherein R* is as defined herein.

In an exemplary embodiment, the compound has a formula which is a memberselected from

wherein R* is as described herein.IIIb. Soft Drugs

Soft drugs (or ante-drugs) are therapeutic agents that undergopredictable metabolism to inactive metabolites after exerting theirtherapeutic effect. Hence, they are obtained by building into themolecule, in addition to the activity, the most desired way in which themolecule is to be deactivated and detoxified.

In a third aspect, the invention provides an oxaborole which comprisesan ester attached to its 5-position moiety. These 5-position oxaboroleesters are metabolically stable in topical applications (such as theskin or nail) and exert their therapeutic action. The 5-positionoxaborole ester is then hydrolyzed by an esterase. Esterases areclassified broadly as cholinesterases (including acetylcholinesterases),carboxylesterases and arylesterases. The mechanism involved follows thegeneral formula:

Highly variable esterase activity is present in a wide variety oforgans, tissues and body fluids. After hydrolysis, the 5-positionoxaborole ester is converted into a 5-position oxaborole acid, which islargely inactive and non-toxic if any drug penetrates the skin andreaches systemic circulation. This so-called soft-drug approach improvesthe therapeutic index of 5-position oxaborole bioactive compounds.

In a third aspect, the invention provides a compound having a structureaccording to the formula:

wherein R* is a member selected from H, a negative charge and apositively charged counterion. R³ and R⁴ are members independentlyselected from H, cyano, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. R⁹,R¹⁰, R¹¹ and R¹² are members independently selected from H, OR²⁰,NR²⁰R²¹, SR²⁰, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)₂NR²⁰R²¹, nitro, halogen,cyano, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. Each R²⁰ and R²¹ are membersindependently selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl. R³and R⁴, together with the atoms to which they are attached, areoptionally joined to form a 4 to 7 membered ring. R⁹ and R¹⁰, togetherwith the atoms to which they are attached, are optionally joined to forma 4 to 7 membered ring. R¹⁰ and R¹¹, together with the atoms to whichthey are attached, are optionally joined to form a 4 to 7 membered ring.R¹¹ and R¹², together with the atoms to which they are attached, areoptionally joined to form a 4 to 7 membered ring. R²⁰ and R²¹, togetherwith the atoms to which they are attached, are optionally joined to forma 4 to 7 membered ring. There is a proviso that R¹⁰ comprises a moietyhaving the structure according to the formula:

wherein R²² is a member selected from H, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In an exemplary embodiment, there is the proviso that the compound isnot

In an exemplary embodiment, there is the proviso that the compound isnot

In an exemplary embodiment, R²² is H. In an exemplary embodiment, R²² isa member selected from substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. In anexemplary embodiment, R²² is a member selected from substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In an exemplary embodiment, there is the proviso that at least onemember selected from R¹⁰ and R¹¹ must comprise a moiety having thestructure according to the formula:

In an exemplary embodiment, R²² is a member selected from substituted orunsubstituted methyl, substituted or unsubstituted ethyl, substituted orunsubstituted propyl, substituted or unsubstituted isopropyl,substituted or unsubstituted butyl.

In an exemplary embodiment, the compound has a structure which is amember selected from:

wherein Y is a member selected from S and O; A is a member selected fromsubstituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl; R^(a), R^(b) and R^(c) are members independently selectedfrom H, OR²⁰, NR²⁰R²¹, SR²⁰, —S(O)R²⁰, —S(O)₂R²⁰, —S(O)₂NR²⁰R²¹,—C(O)R²⁰, —C(O)NR²⁰R²¹, —C(O)OR²², nitro, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein each R²⁰ and R²¹ are membersindependently selected from H, nitro, halogen, cyano, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, with the proviso that R²⁰ and R²¹, togetherwith the atoms to which they are attached, are optionally combined toform a 5- to 7-membered substituted or unsubstituted heterocycloalkylring, with the proviso that at least one member selected from R^(a),R^(b), R^(c) comprises —C(O)OR²².

In an exemplary embodiment, the compound has a structure which is amember selected from:

wherein R*, R^(a), R^(b) and R^(c) are as described herein.

In an exemplary embodiment, the compound has a structure which is amember selected from:

wherein R* is as defined herein.

In an exemplary embodiment, the compound has a structure according tothe formula

wherein X, R*, R^(b) and R^(c) are as described herein, and whereinR^(h) is a halogen. In another exemplary embodiment, R^(h) is fluoro. Inanother exemplary embodiment, R^(h) is chloro. In another exemplaryembodiment, the compound has a structure which is a member selectedfrom:

wherein X, R*, R^(b), R^(c) and R^(h) are as described herein. Inanother exemplary embodiment, the compound has a structure which is amember selected from:

wherein X, R*, R^(b), R^(c) and R^(h) are as described herein.

In an exemplary embodiment, the compound has a structure which is amember selected from:

wherein R* is as defined herein.

IIIc.

In a fourth aspect, the invention provides a compound having a structureaccording to the formula:

wherein R* is a member selected from H, a negative charge and apositively charged counterion, X is CH or N, and R^(d) isaminosubstituted alkyl.

In an exemplary embodiment, R^(d) is —(CR¹⁰R¹¹)_(n)NR¹²R¹³ in which n isa member selected from 1-10, and R¹⁰, R¹¹, R¹² and R¹³ are membersindependently selected from H, OR¹⁴, NR¹⁴R¹⁵, SR¹⁴, —S(O)R¹⁴, —S(O)₂R¹⁴,—S(O)₂NR¹⁴R¹⁵, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁵, nitro, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl wherein each R¹⁴ and R¹⁵ aremembers independently selected from H, nitro, halogen, cyano,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

In an exemplary embodiment, R¹⁰ and R¹¹ are H. In an exemplaryembodiment, R¹² and R¹³ are H. In an exemplary embodiment, n is a memberselected from 1 to 5. In another exemplary embodiment, n is a memberselected from 1 to 3. In an exemplary embodiment, n is 1.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHR¹³ in which n is amember selected from 1-10, and R¹³ is a member selected from H, OR¹⁴,NR¹⁴R¹⁵, SR¹⁴, —S(O)R¹⁴, —S(O)₂R¹⁴, —S(O)₂NR¹⁴R¹⁵, —C(O)R¹⁴—C(O)OR¹⁴,—C(O)NR¹⁴R¹⁵, wherein each R¹⁴ and R¹⁵ are members independentlyselected from H, nitro, halogen, cyano, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHR¹³ in which n is amember selected from 1-10, and R¹³ is —S(O)₂R¹⁴, wherein R¹⁴ is a memberselected from H, unsubstituted alkyl and substituted or unsubstitutedaryl.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHR¹³ in which n is amember selected from 1-10, and R¹³ is —S(O)₂R¹⁴, wherein R¹⁴ isunsubstituted alkyl or substituted or unsubstituted aryl. In anexemplary embodiment, R¹⁴ is unsubstituted C₁ or C₂ or C₃ alkyl. In anexemplary embodiment, R¹⁴ is unsubstituted C₄ or C₅ or C₆ alkyl. In anexemplary embodiment, R¹⁴ is C₁ alkyl.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHR¹³ in which n is amember selected from 1-10, and R¹³ is —S(O)₂R¹⁴, wherein R¹⁴ issubstituted or unsubstituted aryl. In an exemplary embodiment, R¹⁴ issubstituted or unsubstituted phenyl. In an exemplary embodiment, R¹⁴ isunsubstituted phenyl. In an exemplary embodiment, R¹⁴ is phenylsubstituted with at least one halogen and/or at least one unsubstitutedalkyl. In an exemplary embodiment, R^(d) has a structure which is amember selected from

wherein R¹⁴ is chloro or fluoro or unsubstituted C₁ or C₂ or C₃ or C₄alkyl. In an exemplary embodiment, R¹⁴ is chloro or methyl. In anexemplary embodiment, n is 1 or 2 or 3. In an exemplary embodiment, n is1.

In an exemplary embodiment, R^(d) has a structure which is a memberselected from

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NH₂ in which n is amember selected from 1-10. In an exemplary embodiment, n is 1 or 2 or 3or 4 or 5. In an exemplary embodiment, n is 1 or 2 or 3. In an exemplaryembodiment, R^(d) is —CH₂NH₂.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHR¹³ in which n is amember selected from 1-10, and R¹³ is unsubstituted cycloalkyl. In anexemplary embodiment, R¹³ is unsubstituted C₃-C₈ cycloalkyl. In anexemplary embodiment, R¹³ is cyclopentyl or cyclohexyl or cycloheptyl.In an exemplary embodiment, n is 1 or 2 or 3. In an exemplaryembodiment, n is 1. In an exemplary embodiment, n is 1 and R¹³ iscyclohexyl.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHR¹³ in which n is amember selected from 1-10, and R¹³ is unsubstituted alkyl. In anexemplary embodiment, R¹³ is C₁ or C₂ or C₃ alkyl. In an exemplaryembodiment, R¹³ is C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, nis 1 or 2 or 3. In an exemplary embodiment, n is 1. In an exemplaryembodiment, R^(d) is —(CH₂)_(n)NHCH₃. In an exemplary embodiment, R^(d)is —(CH₂)NHCH₃.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NR^(13a)R¹³ in which n isa member selected from 1-10, and R¹³ and R^(13a) are each membersindependently selected unsubstituted alkyl. In an exemplary embodiment,R¹³ and R^(13a) are each members independently selected fromunsubstituted alkyl. In an exemplary embodiment, R¹³ and R^(13a) areeach members independently selected from C₁ or C₂ or C₃ or C₄ or C₅ orC₆ alkyl. In an exemplary embodiment, R¹³ and R^(13a) are each membersindependently selected from C₁ or C₂ or C₃ alkyl. In an exemplaryembodiment, R^(d) is —(CH₂)NR^(13a)R¹³, wherein R¹³ and R^(13a) are eachmembers independently selected from C₁ or C₂ or C₃ alkyl. In anexemplary embodiment, R^(d) is —(CH₂)N(CH₃)₂.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NH(CH₂)_(n1)R¹⁶ in whichn is a member selected from 1-10, n1 is a member selected from 1-10, andR¹⁶ is substituted or unsubstituted aryl. In an exemplary embodiment, n1is 1 or 2 or 3 or 4 or 5. In an exemplary embodiment, n1 is 1. In anexemplary embodiment, R¹⁶ is unsubstituted phenyl. In an exemplaryembodiment, R¹⁶ is phenyl optionally substituted with at least onehalogen. In an exemplary embodiment, R¹⁶ is phenyl optionallysubstituted with at least one halogen. In an exemplary embodiment, R¹⁶is phenyl optionally substituted with at least one chloro or fluoro orbromo. In an exemplary embodiment, R¹⁶ is ortho-bromophenyl ormeta-bromophenyl or para-bromophenyl. In an exemplary embodiment, R^(d)is —CH₂NHCH₂R¹⁶, wherein R¹⁶ is phenyl or ortho-bromophenyl ormeta-bromophenyl.

In an exemplary embodiment, R¹⁶ is phenyl substituted with nitro orcyano or unsubstituted alkoxy or unsubstituted alkyl. In an exemplaryembodiment, R¹⁶ is ortho-cyanophenyl or meta-cyanophenyl orpara-cyanophenyl. In an exemplary embodiment, R¹⁶ is ortho-nitrophenylor meta-nitrophenyl or para-nitrophenyl. In an exemplary embodiment,R^(d) is —CH₂NHCH₂R¹⁶, wherein R¹⁶ is ortho-cyanophenyl ormeta-cyanophenyl or para-cyanophenyl or ortho-nitrophenyl ormeta-nitrophenyl or para-nitrophenyl.

In an exemplary embodiment, R¹⁶ is phenyl substituted with unsubstitutedC₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, R¹⁶is ortho-methylphenyl or meta-methylphenyl or para-methylphenyl. In anexemplary embodiment, R^(d) is —CH₂NHCH₂R¹⁶, wherein R¹⁶ isortho-methylphenyl or meta-methylphenyl or para-methylphenyl.

In an exemplary embodiment, R¹⁶ is phenyl substituted with unsubstitutedC₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyloxy. In an exemplary embodiment,R¹⁶ is ortho-methoxyphenyl or meta-methyloxyphenyl orpara-methoxyphenyl. In an exemplary embodiment, R^(d) is —CH₂NHCH₂R¹⁶,wherein R¹⁶ is ortho-methoxyphenyl or meta-methoxyphenyl orpara-methoxyphenyl.

In an exemplary embodiment, R¹⁶ is unsubstituted C₃ or C₄ or C₅ or C₆ orC₇ or C₈ cycloalkyl. In an exemplary embodiment, R¹⁶ is unsubstitutedcyclohexyl. In an exemplary embodiment, R^(d) is —CH₂NHCH₂R¹⁶, whereinR¹⁶ is cyclohexyl.

In an exemplary embodiment, R¹⁶ is unsubstituted heteroaryl. In anexemplary embodiment, R¹⁶ is unsubstituted pyrrole. In an exemplaryembodiment, R¹⁶ is unsubstituted 2-pyrrole. In an exemplary embodiment,R^(d) is —CH₂NHCH₂R¹⁶ wherein R¹⁶ is 2-pyrrole.

In an exemplary embodiment, R¹⁶ is unsubstituted C₁ or C₂ or C₃ alkyl.In an exemplary embodiment, R¹⁶ is unsubstituted C₄ or C₅ or C₆ alkyl.In an exemplary embodiment, R^(d) is —CH₂NHC(CH₃)₂.

In an exemplary embodiment, R¹⁶ is phenyl substituted with —NHC(O)—R³⁴,wherein R³⁴ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. Inan exemplary embodiment, R¹⁶ is phenyl substituted with —NHC(O)CH₃. Inan exemplary embodiment, R^(d) is —CH₂NHCH₂R¹⁶, wherein R¹⁶ isortho-(CH₃C(O)NH—)phenyl or meta-(CH₃C(O)NH—)phenyl orpara-(CH₃C(O)NH—)phenyl.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)R¹⁴ in which n is amember selected from 1-10, wherein R¹⁴ is unsubstituted alkyl. In anexemplary embodiment, R¹⁴ is unsubstituted C₁ or C₂ or C₃ alkyl. In anexemplary embodiment, R¹⁴ is unsubstituted C₄ or C₅ or C₆ alkyl. In anexemplary embodiment, R¹⁴ is methyl or ethyl or isopropyl or t-butyl or.In an exemplary embodiment, R¹⁴ is C₁ alkyl. In an exemplary embodiment,R^(d) is —(CH₂)NHC(O)CH₃ or —(CH₂)NHC(O)CH₂CH₃ or —(CH₂)NHC(O)CH(CH₃)₂or —(CH₂)NHC(O)C(CH₃)₃.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)R¹⁴ in which n is amember selected from 1-10, wherein R¹⁴ is substituted or unsubstitutedaryl. In an exemplary embodiment, R¹⁴ is unsubstituted phenyl. In anexemplary embodiment, R¹⁴ is phenyl, substituted with nitro or cyano orunsubstituted alkoxy or unsubstituted alkyl. In an exemplary embodiment,R¹⁴ is ortho-cyanophenyl or meta-cyanophenyl or para-cyanophenyl. In anexemplary embodiment, R¹⁴ is ortho-nitrophenyl or meta-nitrophenyl orpara-nitrophenyl. In an exemplary embodiment, R^(d) is —CH₂NHC(O)R¹⁴,wherein R¹⁴ is ortho-cyanophenyl or meta-cyanophenyl or para-cyanophenylor ortho-nitrophenyl or meta-nitrophenyl or para-nitrophenyl.

In an exemplary embodiment, R¹⁴ is phenyl substituted with unsubstitutedC₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, R¹⁴is ortho-methylphenyl or meta-methylphenyl or para-methylphenyl. In anexemplary embodiment, R^(d) is —CH₂NHC(O)R¹⁴, wherein R¹⁴ isortho-methylphenyl or meta-methylphenyl or para-methylphenyl.

In an exemplary embodiment, R¹⁴ is phenyl substituted with unsubstitutedC₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyloxy. In an exemplary embodiment,R¹⁴ is ortho-methoxyphenyl or meta-methyloxyphenyl orpara-methoxyphenyl. In an exemplary embodiment, R^(d) is —CH₂NHC(O)R¹⁴,wherein R¹⁴ is ortho-methoxyphenyl or meta-methoxyphenyl orpara-methoxyphenyl.

In an exemplary embodiment, R¹⁴ is phenyl substituted with a halogen. Inan exemplary embodiment, R¹⁴ is chloro or fluoro. In an exemplaryembodiment, R^(d) is —CH₂NHC(O)R¹⁴, wherein R¹⁴ is ortho-fluorophenyl ormeta-fluorophenyl or para-fluorophenyl.

In an exemplary embodiment, R¹⁴ is phenyl substituted with haloalkyl. Inan exemplary embodiment, the halogen is chloro or fluoro. In anexemplary embodiment, R¹⁴ is phenyl substituted with alkyl substitutedwith three fluorines. In an exemplary embodiment, R¹⁴ is phenylsubstituted with alkyl substituted with two fluorines. In an exemplaryembodiment, R¹⁴ is ortho(trifluoromethyl)phenyl ormeta(trifluoromethyl)phenyl or para(trifluoromethyl)phenyl. In anexemplary embodiment, R^(d) is —CH₂NHC(O)R¹⁴, wherein R¹⁴ is R¹⁴ isortho(trifluoromethyl)phenyl or meta(trifluoromethyl)phenyl orpara(trifluoromethyl)phenyl.

In an exemplary embodiment, R^(d) is—(CH₂)_(n)NHC(O)(CR⁴⁰R⁴¹)_(n9)OC(O)R⁴² in which n is a member selectedfrom 1-10, wherein R⁴⁰ is unsubstituted alkyl, R⁴¹ is unsubstitutedalkyl, R⁴² is unsubstituted alkyl. In an exemplary embodiment, R⁴⁰ orR⁴¹ or R⁴² are each independently selected C₁ or C₂ or C₃ or C₄ or C₅ orC₆ alkyl. In an exemplary embodiment, R⁴⁰ or R⁴¹ or R⁴² are each methyl.In an exemplary embodiment, n9 is 1. In an exemplary embodiment, R^(d)is —(CH₂)_(n)NHC(O)(C(CH₃)(CH₃))OC(O)R⁴², wherein R⁴² is C₁ or C₂ or C₃or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, R^(d) is—(CH₂)_(n)NHC(O)(C(CH₃)(CH₃))OC(O)CH₃.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)R¹⁴ in which n is amember selected from 1-10, wherein R¹⁴ is unsubstituted cycloalkyl. Inan exemplary embodiment, R¹⁴ is unsubstituted C3 or C4 or C5 or C6 or C7or C8 cycloalkyl. In an exemplary embodiment, R¹⁴ is unsubstitutedcyclopentyl or cyclohexyl.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)R¹⁴ in which n is amember selected from 1-10, wherein R¹⁴ is unsubstituted heteroaryl. Inan exemplary embodiment, R¹⁴ is unsubstituted furan. In an exemplaryembodiment, R¹⁴ is unsubstituted 2-furan.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)OR¹⁴ in which n isa member selected from 1-10, wherein R¹⁴ is unsubstituted alkyl. In anexemplary embodiment, R¹⁴ is C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. Inan exemplary embodiment, R¹⁴ is C₄ alkyl. In an exemplary embodiment,R¹⁴ is a member selected from n-butyl, isobutyl, sec-butyl andtert-butyl. In an exemplary embodiment, R^(d) is —(CH₂)NHC(O)OR¹⁴,wherein R¹⁴ is C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)OC(CH₃)₃.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)NR⁴³R⁴⁴ in which nis an integer selected from 1-10, wherein R⁴³ and R⁴⁴ are independentlyselected from H, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl and substituted or unsubstituted aryl. In anexemplary embodiment, R⁴³ and R⁴⁴, together with the nitrogen to whichthey are attached, are joined to form a 3 to 8 membered ring. In anexemplary embodiment, R⁴³ and R⁴⁴, together with the nitrogen to whichthey are attached, are joined to form a 4 to 7 membered ring. In anexemplary embodiment, R⁴³ and R⁴⁴, together with the nitrogen to whichthey are attached, are joined to form a 5 to 6 membered ring. In anexemplary embodiment, n is 1 or 2 or 3. In an exemplary embodiment,R^(d) is

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)NHR⁴⁴ in which n isan integer selected from 1-10, wherein R⁴⁴ is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl andsubstituted or unsubstituted aryl. In an exemplary embodiment, R⁴⁴ isunsubstituted aryl. In an exemplary embodiment, R⁴⁴ is unsubstitutedphenyl. In an exemplary embodiment, R⁴⁴ is aryl, substituted withunsubstituted alkyl. In an exemplary embodiment, R⁴⁴ is aryl,substituted with unsubstituted C₁ or C₂ or C₃ alkyl. In an exemplaryembodiment, R⁴⁴ is aryl, substituted with unsubstituted C₄ or C₅ or C₆alkyl. In an exemplary embodiment, R⁴⁴ is phenyl, substituted withunsubstituted C₁ or C₂ or C₃ alkyl. In an exemplary embodiment, R⁴⁴ isortho methylphenyl or meta methylphenyl or para methylphenyl. In anexemplary embodiment, R^(d) is —(CH₂)NHC(O)NHR⁴⁴, wherein R⁴⁴ is paramethylphenyl.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)NHR⁴⁴ in which n isan integer selected from 1-10, wherein R⁴⁴ is aryl, substituted withunsubstituted alkylamino. In an exemplary embodiment, R⁴⁴ is aryl,substituted with NR⁵⁰R⁵¹, wherein R⁵⁰ and R⁵¹ are each independentlyselected from H and unsubstituted alkyl. In an exemplary embodiment, R⁴⁴is phenyl, substituted with NR⁵⁰R⁵¹, wherein R⁵⁰ and R⁵¹ are eachindependently selected from C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. Inan exemplary embodiment, R⁴⁴ is phenyl, substituted with NR⁵⁰R⁵¹,wherein R⁵⁰ and R⁵¹ are each independently selected from C₁ or C₂ or C₃alkyl. In an exemplary embodiment, R⁴⁴ is ortho (NR⁵⁰R⁵¹)phenyl or meta(NR⁵⁰R⁵¹)phenyl or para (NR⁵⁰R⁵¹)phenyl. In an exemplary embodiment, R⁵⁰is C₁ or C₂ or C₃ alkyl. In an exemplary embodiment, R⁵¹ is C₁ or C₂ orC₃ alkyl. In an exemplary embodiment, R⁵⁰ is C₁ or C₂ or C₃ alkyl. In anexemplary embodiment, R⁴⁴ is phenyl, substituted with N(CH₃)₂. In anexemplary embodiment, R^(d) is —(CH₂)NHC(O)NHR⁴⁴, wherein R⁴⁴ is para(N(CH₃)₂)phenyl.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)(CH₂)_(n10)NR⁴³R⁴⁴in which n is an integer selected from 1-10, n0 is an integer selectedfrom 1-10, wherein R⁴³ and R⁴⁴ are independently selected from H,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl and substituted or unsubstituted aryl. In an exemplaryembodiment, R⁴³ and R⁴⁴, together with the nitrogen to which they areattached, are joined to form a 3 to 8 membered ring. In an exemplaryembodiment, R⁴³ and R⁴⁴, together with the nitrogen to which they areattached, are joined to form a 4 to 7 membered ring. In an exemplaryembodiment, R⁴³ and R⁴⁴, together with the nitrogen to which they areattached, are joined to form a 5 to 6 membered ring. In an exemplaryembodiment, n is 1 or 2 or 3. In an exemplary embodiment, n10 is 1 or 2or 3. In an exemplary embodiment, R^(d) is —(CH₂NHC(O)(CH₂)_(n10)NR⁴³R⁴⁴

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)NHR⁴⁴ in which n isan integer selected from 1-10, wherein R⁴⁴ is aryl, substituted withhalogen. In an exemplary embodiment, R⁴⁴ is phenyl, substituted withhalogen. In an exemplary embodiment, R⁴⁴ is ortho (halogen)phenyl ormeta (halogen)phenyl or para (halogen)phenyl. In an exemplaryembodiment, R⁴⁴ is ortho (chloro)phenyl or meta (chloro)phenyl or para(chloro)phenyl. In an exemplary embodiment, R⁴⁴ is ortho (fluoro)phenylor meta (fluoro)phenyl or para (fluoro)phenyl. In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)NHR⁴⁴, wherein R⁴⁴ is para(chloro)phenyl.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)NHR⁴⁴ in which n isan integer selected from 1-10, wherein R⁴⁴ is unsubstituted aryl. In anexemplary embodiment, R⁴⁴ is unsubstituted phenyl. In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)NHR⁴⁴, wherein R⁴⁴ is unsubstitutedphenyl.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)NHR⁴⁴ in which n isan integer selected from 1-10, wherein R⁴⁴ is unsubstituted alkyl. In anexemplary embodiment, R⁴⁴ is C₁ or C₂ or C₃ alkyl. In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)NHR⁴⁴, wherein R⁴⁴ is C₄ or C₅ or C₆alkyl. In an exemplary embodiment, R^(d) is —(CH₂)NHC(O)NHR⁴⁴, whereinR⁴⁴ is ethyl.

In an exemplary embodiment, R^(d) is—(CH₂)_(n)NHC(O)(CR⁵²R⁵³)_(n11)NR⁵⁴R⁵⁵ in which n is an integer selectedfrom 1-10, n11 is an integer selected from 1-10, wherein R⁵² and R⁵³ areindependently selected from H and alkyl optionally substituted witharyl, and wherein R⁵⁴ and R⁵⁵ are independently selected from H,unsubstituted alkyl, and —C(O)OR⁵⁶, wherein R⁵⁶ is unsubstituted alkyl.

In an exemplary embodiment, R^(d) is —(CH₂)NHC(O)(CH₂)_(n11)NR⁵⁴R⁵⁵ inwhich n11 is an integer selected from 1-10, and wherein R⁵⁴ and R⁵⁵ areindependently selected from H, unsubstituted alkyl, and —C(O)OR⁵⁶,wherein R⁵⁶ is unsubstituted alkyl. In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)(CH₂)NHR⁵⁵ and wherein R⁵⁵ is —C(O)OR⁵⁶, wherein R⁵⁶ isunsubstituted alkyl. In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)(CH₂)NHR⁵⁵ and wherein R⁵⁵ is —C(O)OR⁵ wherein R⁵⁶ is C₁ orC₂ or C₃ alkyl. In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)(CH₂)NHR⁵⁵ and wherein R⁵⁵ is —C(O)OR⁵⁶, wherein R⁵⁶ is C₄or C₅ or C₆ alkyl.

In an exemplary embodiment, R^(d) is —(CH₂)NHC(O)(CH₂)NR⁵⁴R⁵⁵ andwherein R⁵⁴ is unsubstituted alkyl, and R⁵⁵ is —C(O)OR⁵⁶, wherein R⁵⁶ isunsubstituted alkyl. In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)(CH₂)NR⁵⁴R⁵⁵ and wherein R⁵⁴ is C₁ or C₂ or C₃ or C₄ or C₅or C₆ alkyl, R⁵⁵ is —C(O)OR⁵⁶, wherein R⁵⁶ is C₁ or C₂ or C₃ or C₄ or C₅or C₆ alkyl. In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)(CH₂)NR⁵⁴R⁵⁵ and wherein R⁵⁴ is C₁ alkyl, R⁵⁵ is —C(O)OR⁵⁶,wherein R⁵⁶ is C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)(CH₂)NR⁵⁴R⁵⁵ and wherein R⁵⁴ is C₁ orC₂ or C₃ alkyl, R⁵⁵ is —C(O)OR⁵⁶, wherein R⁵⁶ is C₃ or C₄ or C₅ alkyl.In an exemplary embodiment, R^(d) is —(CH₂)NHC(O)(CH₂)NR⁵⁴R⁵⁵ andwherein R⁵⁴ is C₁ alkyl, R⁵⁵ is —C(O)OR⁵⁶, wherein R⁵⁶ is C₄ alkyl.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)(CH₂)_(n11)NR⁵⁴R⁵⁵in which n is an integer selected from 1-10, n11 is an integer selectedfrom 1-10, and wherein R⁵⁴ and R⁵⁵ are independently selected from H andunsubstituted alkyl. In an exemplary embodiment, R^(d) is—(CH₂)_(n)NHC(O)(CH₂)_(n11)NH₂. In an exemplary embodiment, n is 1 or 2or 3. In an exemplary embodiment, n11 is 1 or 2 or 3. In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)(CH₂)NH₂. In an exemplary embodiment,R^(d) is —(CH₂)_(n)NHC(O)(CH₂)_(n11)NHR⁵⁵ in which n is an integerselected from 1-10, n11 is an integer selected from 1-10, and whereinR⁵⁵ is unsubstituted alkyl. In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)(CH₂)NHR⁵⁵ in which R⁵⁵ is unsubstituted alkyl. In anexemplary embodiment, R^(d) is —(CH₂)NHC(O)(CH₂)NHR⁵⁵ in which R⁵⁵ is C₁or C₂ or C₃ alkyl. In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)(CH₂)NHR⁵⁵ in which R⁵⁵ is C₄ or C₅ or C₆ alkyl. In anexemplary embodiment, R^(d) is —(CH₂)NHC(O)(CH₂)NHCH₃.

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)(CH₂)_(n11)NR⁵⁴R⁵⁵in which n is an integer selected from 1-10, n11 is an integer selectedfrom 1-10, and wherein R⁵⁴ and R⁵⁵ are independently selectedunsubstituted alkyl. In an exemplary embodiment, R⁵⁴ and R⁵⁵ are eachmembers independently selected from C₁ or C₂ or C₃ or C₄ or C₅ or C₆alkyl. In an exemplary embodiment, R⁵⁴ and R⁵⁵ are each membersindependently selected from C₁ or C₂ or C₃ alkyl. In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)(CH₂)NR⁵⁴R⁵⁵, wherein R⁵⁴ and R⁵⁵ areeach members independently selected from C₁ or C₂ or C₃ alkyl. In anexemplary embodiment, R^(d) is —(CH₂)NHC(O)(CH₂)N(CH₃)₂.

In an exemplary embodiment, R^(d) is—(CH₂)_(n)NHC(O)(CHR⁵³)_(n11)NR⁵⁴R⁵⁵ in which n is an integer selectedfrom 1-10, n11 is an integer selected from 1-10, wherein R⁵³ is alkyl,and wherein R⁵⁴ and R⁵⁵ are independently selected from H, unsubstitutedalkyl, and —C(O)OR⁵⁶, wherein R⁵⁶ is unsubstituted alkyl. In anexemplary embodiment, n is 1 or 2 or 3 and n11 is 1 or 2 or 3. In anexemplary embodiment, n is 1 and n11 is 1. In an exemplary embodiment,R^(d) is —(CH₂)_(n)NHC(O)(CHR⁵³)_(n11)NH₂ in which n is an integerselected from 1-10, n11 is an integer selected from 1-10, wherein R⁵³ isalkyl. In an exemplary embodiment, R^(d) is —(CH₂)NHC(O)CH(R⁵³)(NH₂) inwhich R⁵³ is alkyl. In an exemplary embodiment, R⁵³ is C₁ or C₂ or C₃ orC₄ or C₅ or C₆ alkyl. In an exemplary embodiment, R⁵³ is C₁ or C₂ or C₃alkyl. In an exemplary embodiment, R^(d) is —(CH₂)NHC(O)CH(R⁵³)(NH₂) inwhich R⁵³ is C₁ or C₂ or C₃ or C₄ alkyl. In an exemplary embodiment,R^(d) is —(CH₂)NHC(O)CH(R⁵³)(NH₂) in which R⁵³ is C₄ alkyl. In anexemplary embodiment, R^(d) is —(CH₂)NHC(O)CH(CH₃)(NH₂). In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)CH(NH₂)(CH₂CH(CH₃)₂).

In an exemplary embodiment, R^(d) is—(CH₂)_(n)NHC(O)(CHR⁵³)_(n11)NR⁵⁴R⁵⁵ in which n is an integer selectedfrom 1-10, n11 is an integer selected from 1-10, wherein R⁵³ is alkylsubstituted with aryl, and wherein R⁵⁴ and R⁵⁵ are independentlyselected unsubstituted alkyl. In an exemplary embodiment, n is 1 or 2 or3 and n11 is 1 or 2 or 3. In an exemplary embodiment, n is 1 and n11is 1. In an exemplary embodiment, R^(d) is—(CH₂)_(n)NHC(O)(CHR⁵³)_(n11)NR⁵⁴R⁵⁵ in which n is an integer selectedfrom 1-10, n11 is an integer selected from 1-10, wherein R⁵³ is alkylsubstituted with aryl. In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)CH(R⁵³)(NR⁵⁴R⁵⁵) in which R⁵³ is alkyl substituted witharyl. In an exemplary embodiment, R⁵³ is (CH₂)_(n12)-Ph, wherein n12 isan integer selected from 1-10. In an exemplary embodiment, n is 1 or 2or 3, n11 is 1 or 2 or 3 and n12 is 1 or 2 or 3. In an exemplaryembodiment, n is 1, n11 is 1 and n12 is 1. In an exemplary embodiment,R^(d) is —(CH₂)NHC(O)CH(CH₂-Ph)(NR⁵⁴R⁵⁵) in which R⁵⁴ or R⁵⁵ is C₁ or C₂or C₃ or C₄ alkyl. In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)CH((CH₂)_(n12)-Ph)(N(CH₃)₂). In an exemplary embodiment,R^(d) is —(CH₂)NHC(O)CH(CH₂-Ph)(N(CH₃)₂).

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)R⁵⁸ in which n isan integer selected from 1-10, and R⁵⁸ is a member selected from

wherein R⁵⁹ is H or unsubstituted alkyl or C(O)OR⁵⁶, wherein R⁵⁶ isunsubstituted alkyl. In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)R⁵⁸ in which R⁵⁸ is

In an exemplary embodiment, R^(d) is —(CH₂)NHC(O)R⁵⁸ in which R⁵⁸ is

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)(CHR⁵³)_(n11)NHR⁵⁵in which n is an integer selected from 1-10, n11 is an integer selectedfrom 1-10, wherein R⁵³ is alkyl, and wherein R⁵⁵ is —C(O)OR⁵⁶, whereinR⁵⁶ is unsubstituted alkyl. In an exemplary embodiment, n is 1 or 2 or 3and n11 is 1 or 2 or 3. In an exemplary embodiment, n is 1 and n11 is 1.In an exemplary embodiment, R^(d) is —(CH₂)NHC(O)CH(R⁵³)(NHC(O)OR⁵⁶) inwhich R⁵³ is C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl and R⁵⁶ is C₁ or C₂or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, R⁵³ is C₁ orC₂ or C₃ alkyl. In an exemplary embodiment, R⁵⁶ is C₄ or C₅ or C₆ alkyl.In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)CH(CH₂CH(CH₃)₂)(NHC(O)OR⁵⁶). In an exemplary embodiment,R^(d) is —(CH₂)NHC(O)CH(R⁵³)(NHC(O)OC(CH₃)₃). In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)CH(CH₂CH(CH₃)₂)(NHC(O)OC(CH₃)₃).

In an exemplary embodiment, R^(d) is —(CH₂)_(n)NHC(O)(CHR⁵³)_(n11)NH₂ inwhich n is an integer selected from 1-10, n11 is an integer selectedfrom 1-10, wherein R⁵³ is unsubstituted alkyl, optionally substitutedwith aryl. In an exemplary embodiment, n is 1 or 2 or 3 and n11 is 1 or2 or 3. In an exemplary embodiment, n is and n11 is 1. In an exemplaryembodiment, R^(d) is —(CH₂)_(n)NHC(O)(CHR⁵³)_(n11)NH₂ in which n is aninteger selected from 1-10, n11 is an integer selected from 1-10,wherein R⁵³ is (CH₂)_(n12)-Ph, wherein n12 is an integer selected from1-10. In an exemplary embodiment, n is 1 or 2 or 3, n11 is 1 or 2 or 3and n12 is 1 or 2 or 3. In an exemplary embodiment, n is 1, n11 is 1 andn12 is 1. In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)CH[(CH₂)-Ph])(NH₂).

In an exemplary embodiment, R^(d) is—(CH₂)_(n)NHC(O)(CHR⁵³)_(n11)NH(C(O)OR⁵⁶) in which n is an integerselected from 1-10, n11 is an integer selected from 1-10, wherein R⁵⁶ isC₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, and R⁵³ is unsubstituted alkyl.In an exemplary embodiment, n is 1 or 2 or 3 and n11 is 1 or 2 or 3. Inan exemplary embodiment, n is 1 and n11 is 1. In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)(CHR⁵³)NH(C(O)OR⁵⁶), wherein R⁵⁶ is C₄alkyl, and R⁵³ is C₁ or C₂ or C₃ or C₄ alkyl. In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)CH(CH₃)(NH(C(O)OR⁵⁶)). In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)CH(R⁵³)(NH(C(O)OC(CH₃)₃)). In anexemplary embodiment, R^(d) is —(CH₂)NHC(O)CH(CH₃))NH(C(O)OC(CH₃)₃).

In an exemplary embodiment, R^(d) is—(CH₂)_(n)NHC(O)(CHR⁵³)_(n11)NH(C(O)OR⁵⁶) in which n is an integerselected from 1-10, n11 is an integer selected from 1-10, wherein R⁵⁶ isC₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, and R⁵³ is alkyl substitutedwith aryl. In an exemplary embodiment, n is 1 or 2 or 3 and n11 is 1 or2 or 3. In an exemplary embodiment, n is 1 and n11 is 1. In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)(CHR⁵³)NH(C(O)OR⁵⁶), wherein R⁵⁶ is C₄alkyl, and R⁵³ is (CH₂)_(n12)-Ph, wherein n₁₂ is an integer selectedfrom 1-10. In an exemplary embodiment, R^(d) is—(CH₂)NHC(O)CH((CH₂)-Ph)(NH(C(O)OR⁵⁶)). In an exemplary embodiment,R^(d) is —(CH₂)NHC(O)CH(R⁵³)(NH(C(O)OC(CH₃)₃)). In an exemplaryembodiment, R^(d) is —(CH₂)NHC(O)CH((CH₂)-Ph))(NH(C(O)OC(CH₃)₃)).

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R^(d) is as defined herein.

In an exemplary embodiment, compound has a structure according to theformula:

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R* is as defined herein.

In an exemplary embodiment, the compound has a structure which is amember selected from:

wherein R* is as defined herein.

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R* is as defined herein.

IIId.

In a fifth aspect, the invention provides a compound having a structureaccording to the formula:

wherein Y is a member selected from S and O; R* is a member selectedfrom H, a negative charge and a positively charged counterion; R^(c) isa member selected from substituted or unsubstituted hydroxyalkyl, —C(O)Hand —C(O)NR²⁰R²¹. Each R²⁰ and R²¹ are members independently selectedfrom H, nitro, halogen, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.There is a proviso that R²⁰ and R²¹, together with the atoms to whichthey are attached, are optionally combined to form a 5- to 7-memberedsubstituted or unsubstituted heterocycloalkyl ring.

In an exemplary embodiment, compound has a structure according to theformula:

wherein R^(e) is as defined herein.

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R* is as defined herein, and R^(e) is substituted orunsubstituted hydroxyalkyl. In an exemplary embodiment, R^(e) isunsubstituted hydroxyalkyl. In an exemplary embodiment, R^(e) isunsubstituted C₁-C₆ hydroxyalkyl. In an exemplary embodiment, R^(e) isunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ hydroxyalkyl. In anexemplary embodiment, the compound has a structure which is

wherein R* is as defined herein.

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R* is as defined herein, and R^(e) is C(O)H. In an exemplaryembodiment, the compound has a structure which is

wherein R* is as described herein.

In an exemplary embodiment, the compound has a structure having thefollowing formula:

wherein R* is as defined herein, and with the proviso that both R²⁰ andR²¹ are not both members selected from substituted or unsubstitutedalkyl, and with the proviso that R²⁰ and R²¹, together with the atoms towhich they are attached, are not optionally combined to form asubstituted or unsubstituted morpholino ring. In an exemplaryembodiment, there is the proviso that both R²⁰ and R²¹ are not bothmembers selected from unsubstituted alkyl. In an exemplary embodiment,there is the proviso that both R²⁰ and R²¹ are not both ethyl.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R* is as defined herein, R²⁰ and R²¹ are independently selectedunsubstituted alkyl. In an exemplary embodiment, there is a proviso thateach R²⁰ and R²¹ is not unsubstituted C₄-C₆ alkyl. In an exemplaryembodiment, there is a proviso that each R²⁰ and R²¹ is notunsubstituted C₁-C₃ alkyl. In an exemplary embodiment, there is aproviso that both R²⁰ and R²¹ are not methyl. In an exemplaryembodiment, there is a proviso that both R²⁰ and R²¹ are not ethyl. Inan exemplary embodiment, there is a proviso that both R²⁰ and R²¹ arenot n-propyl. In an exemplary embodiment, the compound is

wherein each R²⁰ and R²¹ is unsubstituted C₄-C₆ alkyl. In an exemplaryembodiment, there is a proviso that the compound is not

wherein each R²⁰ and R²¹ is unsubstituted C₁-C₃ alkyl. In an exemplaryembodiment, there is a proviso that the compound is not

wherein both R²⁰ and R²¹ are methyl. In an exemplary embodiment, thereis a proviso that the compound is not

wherein both R²⁰ and R²¹ are ethyl. In an exemplary embodiment, there isa proviso that the compound is not

wherein both R²⁰ and R²¹ are n-propyl.

In an exemplary embodiment, the compound has a structure according to:

wherein R*, R²⁰ and R²¹ are as described herein.

In an exemplary embodiment, the compound is:

wherein R* is as described herein. In an exemplary embodiment, thecompound is:

wherein R* is as described herein. In an exemplary embodiment, thecompound is:

wherein R* is as described herein.

In an exemplary embodiment, the compound does not have a structureaccording to the following formula:

wherein R* is as described herein.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R* is as defined herein, R²⁰ is NH₂. In an exemplary embodiment,the compound has a structure according to the following formula:

wherein R* is as defined herein.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R* is as defined herein, R²⁰ is tetrahydro-furan-2-ylmethyl. Inan exemplary embodiment, the compound has a structure according to:

wherein R²⁰ is tetrahydro-furan-2-ylmethyl.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R* is as defined herein, R²⁰ is —NC(O)OR⁵⁶, wherein R⁵⁶ isunsubstituted alkyl. In an exemplary embodiment, R⁵⁶ is a memberselected from C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplaryembodiment, the compound has a structure according to:

wherein R²⁰ is NC(O)OR⁵⁶. In an exemplary embodiment, R⁵⁶ is tert-butyl.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R* is as defined herein, R⁶¹ is unsubstituted alkyl. In anexemplary embodiment, R⁶¹ is C₁, or C₂ or C₃ alkyl. In an exemplaryembodiment, the compound has a structure according to:

wherein R⁶¹ is as described herein. In an exemplary embodiment, R⁶¹ ismethyl.

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R* is as defined herein, and R^(e) is substituted orunsubstituted alkyloxy. In an exemplary embodiment, R^(e) isunsubstituted alkyloxy. In an exemplary embodiment, R^(e) isunsubstituted C₁-C₆ alkyloxy. In an exemplary embodiment, R^(e) isunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyloxy. In an exemplaryembodiment, the compound has a structure which is

wherein R* is as defined herein.

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R* is as defined herein, and R^(e) is NO₂. In an exemplaryembodiment, the compound has a structure which is

wherein R* is as defined herein.

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R* is as defined herein, and R^(e) is NH₂. In an exemplaryembodiment, the compound has a structure which is

wherein R* is as defined herein.

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R* is as defined herein, and R^(e) is R⁶⁰S(O)₂NH—, wherein R⁶⁰is unsubstituted alkyl. In an exemplary embodiment, R⁶⁰ is methyl. In anexemplary embodiment, the compound has a structure which is

wherein R* is as defined herein.

In an exemplary embodiment, the compound has a structure according tothe formula:

wherein R* is as defined herein, and R^(f) is substituted orunsubstituted alkyl. In an exemplary embodiment, R^(f) is unsubstitutedalkyl. In an exemplary embodiment, R^(f) is unsubstituted C₁-C₆ alkyl.In an exemplary embodiment, R^(f) is unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ alkyl. In an exemplary embodiment, R^(f) is unsubstituted C₁or C₂ or C₃ alkyl. In an exemplary embodiment, R^(f) is methyl or ethylor isopropyl. In an exemplary embodiment, the compound has a structurewhich is

wherein R* is as defined herein.

In an exemplary embodiment, the compound has a structure which is amember selected from:

wherein R* and R^(e) are as described herein.

In an exemplary embodiment, the compound has a structure which is amember selected from:

wherein R* and R^(e) are as described herein.

In an exemplary embodiment, R^(e) is —C(O)NR²⁰R²¹, wherein each R²⁰ andR²¹ is a member selected from H, hydroxyalkyl, substituted orunsubstituted aminoalkyl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroarylalkyl, or R²⁰ and R²¹, along withthe nitrogen to which they are attached, are optionally joined to form asubstituted or unsubstituted piperazinyl ring. In an exemplaryembodiment, R²⁰ is H. In an exemplary embodiment, R²¹ is a memberselected from unsubstituted hydroxyalkyl, substituted or unsubstitutedaminoalkyl, unsubstituted phenylalkyl, N-substituted aminoalkyl. In anexemplary embodiment, R²⁰ is H, and R²¹ is unsubstituted alkyl. In anexemplary embodiment, R²⁰ is H, and R²¹ is unsubstituted C₁-C₆ alkyl. Inan exemplary embodiment, R²⁰ is H, and R²¹ is C₁ or C₂ or C₃ or C₄ or C₅or C₆ alkyl. In an exemplary embodiment, R²⁰ and R²¹, along with thenitrogen to which they are attached, are joined to form an unsubstitutedpiperazinyl ring. In an exemplary embodiment, R²⁰ and R²¹, along withthe nitrogen to which they are attached, are joined to form aN-substituted piperazinyl ring. In an exemplary embodiment, theN-substituted piperazinyl ring is substituted with unsubstituted C₁-C₆alkyl and unsubstituted C₁-C₆ alkylcarbonyl. In an exemplary embodiment,R²⁰ is H, and R²¹ is a member selected from ortho-unsubstitutedalkylbenzyl or meta-unsubstitutedalkylbenzyl or para-unsubstitutedalkylbenzyl. In an exemplary embodiment, R²⁰ is H, and R²¹ isparamethylbenzyl. In an exemplary embodiment, R²⁰ is H, and R²¹ is amember selected from ortho-alkoxybenzyl or meta-alkoxybenzyl orpara-alkoxybenzyl. In an exemplary embodiment, R²⁰ is H, and R²¹ is amember selected from ortho-methoxybenzyl or meta-methoxybenzyl orpara-methoxybenzyl. In an exemplary embodiment, R²⁰ is H, and R²¹ ispara-methoxybenzyl. In an exemplary embodiment, R²⁰ is H, and R²¹ isphenyl. In an exemplary embodiment, R²⁰ is H, and R²¹ is cycloalkyl. Inan exemplary embodiment, R²⁰ is H, and R²¹ is cyclopropyl. In anexemplary embodiment, R²⁰ is H, and R²¹ is cyclobutyl. In an exemplaryembodiment, R²⁰ is H, and R²¹ is cyclopentyl. In an exemplaryembodiment, R²⁰ is H, and R²¹ is cyclohexyl. In an exemplary embodiment,R²⁰ is H, and R²¹ is CH₃. In an exemplary embodiment, R²⁰ is CH₃, andR²¹ is CH₃.

In an exemplary embodiment, R^(e) is a member selected from

In an exemplary embodiment, the compound is a member selected fromN-Benzyl-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide,

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-N-(2-hydroxy-ethyl)-benzamide

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-N-pyridin-2-ylmethyl-benzamide

[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-(4-methyl-piperazin-1-yl)-methanone

1-{4-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoyl]-piperazin-1-yl}-ethanone

N-(2-Dimethylamino-ethyl)-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide

N,N-diethyl-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinamide

N-Ethyl-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinamide

5-(5-(Hydroxymethyl)pyridin-2-yloxy)benzo[c][1,2]oxaborol-1 (3H)-ol

6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinaldehyde

and(Z)-N-((6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)pyridin-3-yl)methylene)-2-methylpropan-2-amineoxide

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein X is a member selected from N, CH or C(O)R²², R²² is a memberselected from alkyl, optionally substituted with dialkylamino, and R* isas described herein. In an exemplary embodiment, the compound has astructure according to:

wherein R²² is unsubstituted alkyl, and R* is as described herein. In anexemplary embodiment, R²² is unsubstituted C₁-C₆ alkyl. In an exemplaryembodiment, R²² is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl.In an exemplary embodiment, R²² is unsubstituted C₁ alkyl. In anexemplary embodiment, R²² is unsubstituted C₂ alkyl. In an exemplaryembodiment, R²² is unsubstituted C₃ alkyl. In an exemplary embodiment,R²² is isopropyl. In an exemplary embodiment, R²² is dialkylaminoalkyl.In an exemplary embodiment, R²² is dialkylaminoethyl. In an exemplaryembodiment, R²² is dimethylaminoalkyl. In an exemplary embodiment, R²²is dimethylaminoethyl.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R²³ is halogen, and R* is as described herein. In an exemplaryembodiment, the compound has a structure according to:

wherein R²³ is halogen, and R* is as described herein. In an exemplaryembodiment, R²³ is fluoro or chloro.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R²⁴ is unsubstituted alkyl or halosubstituted alkyl, and R* isas described herein. In an exemplary embodiment, the compound has astructure according to:

wherein R²⁴ is unsubstituted alkyl or halosubstituted alkyl, and R* isas described herein. In an exemplary embodiment, R²⁴ is unsubstitutedC₁-C₆ alkyl or halosubstituted C₁-C₆ alkyl. In an exemplary embodiment,R²⁴ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl. In anexemplary embodiment, R²⁴ is halosubstituted C₁ or C₂ or C₃ or C₄ or C₅or C₆ alkyl. In an exemplary embodiment, R²⁴ is fluorosubstituted C₁ orC₂ or C₃ or C₄ or C₅ or C₆ alkyl. In an exemplary embodiment, R²⁴ istrifluoromethyl. In an exemplary embodiment, R²⁴ is methyl.

In an exemplary embodiment, the compound is

wherein R* is as described herein. In an exemplary embodiment, thecompound is

wherein R* is as described herein.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R²⁸ or R²⁹ are independently selected unsubstituted alkyl, andR* is as described herein. In an exemplary embodiment, the compound hasa structure which is a member selected from:

In an exemplary embodiment, R²⁸ is ethyl. In an exemplary embodiment,R²⁹ is ethyl.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein R³⁰ is H and unsubstituted alkyl, and R* is as described herein.In an exemplary embodiment, the compound has a structure according to:

wherein R³⁰ is unsubstituted alkyl, and R* is as described herein. In anexemplary embodiment, R³⁰ is methyl.

In an exemplary embodiment, the compound has a structure according tothe following formula:

In an exemplary embodiment, the compound has a structure which is listedin FIG. 1, or a salt thereof. In an exemplary embodiment, the compoundhas a structure which is listed in FIG. 2, or a salt thereof. In anexemplary embodiment, the compound has a structure which is listed inFIG. 3, or a salt thereof. In an exemplary embodiment, the compound hasa structure which is listed in FIG. 4, or a salt thereof. In anexemplary embodiment, the compound has a structure which is listed inFIG. 5, or a salt thereof. In an exemplary embodiment, the compound hasa structure which is listed in FIG. 6, or a salt thereof. In anexemplary embodiment, the compound has a structure which is listed inFIG. 7, or a salt thereof.

In an exemplary embodiment, for the compound of any formula describedherein, R* is H.

In another exemplary embodiment, the invention provides poly- ormulti-valent species of the compounds of the invention. In an exemplaryembodiment, the invention provides a dimer of the compounds describedherein. In an exemplary embodiment, the invention provides a dimer ofthe compounds described herein. In an exemplary embodiment, theinvention provides a dimer of a compound which is a member selected fromD1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16,D17, D18, D19, D20, D21, D22, D23, D24, D25, D26, D27, D28, D29, D30,D31, D32, D33, D34, D35, D36, D37, D38, D39, D40, D41, D42, D43, D44,D45, D46, D47, D48, D49, D50, D51, D52, D53, D54, D55, D56, D57, D58,D59, D60, D61, D62, D63, D64, D65, D66, D67, D68, D69, D70, D71, D72,D73, D74, D75, D76, D77, D78, D79, D80, D81, D82, D83, D84, D85, D86,D87, D88, D89, D90, D91, D92, D93, D94, D95, D96, D97, D98, D99, D100,D101, D102, D103, D104, D105, D106, D107, D108, D109, D110, D111, D112,D113, D114, D115, D116, D117, D118, D119, D120, D121, D122, D123, D124,D125, D126, D127, D128, D129, D130, D131, D132, D133, D134, D135, D136,D137, D138, D139, D140, D141, D142, D143, D144, D145, D146, D147, D148,D149, D150, D151, D152, D153, D154, D155, D156, D157, D158, D159, D160,D161, D162, D163, D164, D165, D166, D167, D168, D169, D170, D171, D172,D173, D174, D175, D176, D177, D178, D179, D180, D181, D182, D183, D184,D185, D186, D187, D188, D189, D190, D191, D192, D193, D194, D195, D196,D197, D198, D199, D200, D201, D202, D203, D204, D205, D206, D207, D208,D209, D210, D211, D212, D213, D214, D215, D216, D217, D218, D219, D220,D221, D222, D223, D224, D225, D226, D227, D228 and D229.

In an exemplary embodiment, the invention provides an anhydride of thecompounds described herein. In an exemplary embodiment, the inventionprovides an anhydride of the compounds described herein. In an exemplaryembodiment, the invention provides an anhydride of a compound which is amember selected from D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12,D13, D14, D15, D16, D17, D18, D19, D20, D21, D22, D23, D24, D25, D26,D27, D28, D29, D30, D31, D32, D33, D34, D35, D36, D37, D38, D39, D40,D41, D42, D43, D44, D45, D46, D47, D48, D49, D50, D51, D52, D53, D54,D55, D56, D57, D58, D59, D60, D61, D62, D63, D64, D65, D66, D67, D68,D69, D70, D71, D72, D73, D74, D75, D76, D77, D78, D79, D80, D81, D82,D83, D84, D85, D86, D87, D88, D89, D90, D91, D92, D93, D94, D95, D96,D97, D98, D99, D100, D101, D102, D103, D104, D105, D106, D107, D108,D109, D110, D111, D112, D113, D114, D115, D116, D117, D118, D119, D120,D121, D122, D123, D124, D125, D126, D127, D128, D129, D130, D131, D132,D133, D134, D135, D136, D137, D138, D139, D140, D141, D142, D143, D144,D145, D146, D147, D148, D149, D150, D151, D152, D153, D154, D155, D156,D157, D158, D159, D160, D161, D162, D163, D164, D165, D166, D167, D168,D169, D170, D171, D172, D173, D174, D175, D176, D177, D178, D179, D180,D181, D182, D183, D184, D185, D186, D187, D188, D189, D190, D191, D192,D193, D194, D195, D196, D197, D198, D199, D200, D201, D202, D203, D204,D205, D206, D207, D208, D209, D210, D211, D212, D213, D214, D215, D216,D217, D218, D219, D220, D221, D222, D223, D224, D225, D226, D227, D228and D229.

In an exemplary embodiment, the invention provides a trimer of thecompounds described herein. In an exemplary embodiment, the inventionprovides a trimer of the compounds described herein. In an exemplaryembodiment, the invention provides a trimer of a compound which is amember selected from D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12,D13, D14, D15, D16, D17, D18, D19, D20, D21, D22, D23, D24, D25, D26,D27, D28, D29, D30, D31, D32, D33, D34, D35, D36, D37, D38, D39, D40,D41, D42, D43, D44, D45, D46, D47, D48, D49, D50, D51, D52, D53, D54,D55, D56, D57, D58, D59, D60, D61, D62, D63, D64, D65, D66, D67, D68,D69, D70, D71, D72, D73, D74, D75, D76, D77, D78, D79, D80, D81, D82,D83, D84, D85, D86, D87, D88, D89, D90, D91, D92, D93, D94, D95, D96,D97, D98, D99, D100, D101, D102, D103, D104, D105, D106, D107, D108,D109, D110, D111, D112, D113, D114, D115, D116, D117, D118, D119, D120,D121, D122, D123, D124, D125, D126, D127, D128, D129, D130, D131, D132,D133, D134, D135, D136, D137, D138, D139, D140, D141, D142, D143, D144,D145, D146, D147, D148, D149, D150, D151, D152, D153, D154, D155, D156,D157, D158, D159, D160, D161, D162, D163, D164, D165, D166, D167, D168,D169, D170, D171, D172, D173, D174, D175, D176, D177, D178, D179, D180,D181, D182, D183, D184, D185, D186, D187, D188, D189, D190, D191, D192,D193, D194, D195, D196, D197, D198, D199, D200, D201, D202, D203, D204,D205, D206, D207, D208, D209, D210, D211, D212, D213, D214, D215, D216,D217, D218, D219, D220, D221, D222, D223, D224, D225, D226, D227, D228and D229.

In an exemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof, or a combination thereof.In an exemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or asalt thereof. In an exemplary embodiment, the salt is a pharmaceuticallyacceptable salt. In an exemplary embodiment, the invention provides acompound described herein, or a hydrate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or asolvate thereof. In an exemplary embodiment, the invention provides acompound described herein, or a prodrug thereof. In an exemplaryembodiment, the invention provides a salt of a compound describedherein. In an exemplary embodiment, the invention provides apharmaceutically acceptable salt of a compound described herein. In anexemplary embodiment, the invention provides a hydrate of a compounddescribed herein. In an exemplary embodiment, the invention provides asolvate of a compound described herein. In an exemplary embodiment, theinvention provides a prodrug of a compound described herein.

In an exemplary embodiment, alkyl is a member selected from linear alkyland branched alkyl. In another exemplary embodiment, heteroalkyl is amember selected from linear heteroalkyl and branched heteroalkyl.

Additional compounds which are useful in the methods of the inventionare disclosed in U.S. Prov. Pat. App. 60/654,060; Filed Feb. 16, 2005(Attorney Docket No. 064507-5014PR); U.S. patent application Ser. No.11/357,687, Filed Feb. 16, 2006 (Attorney Docket No. 064507-5014US);U.S. patent application Ser. No. 11/505,591, Filed Aug. 16, 2006(Attorney Docket No. 064507-5014US01), U.S. Prov. Pat. App. 60/823,888filed on Aug. 29, 2006 and 60/774,532 filed on Feb. 16, 2006 (AttorneyDocket No. 064507-5016PR and 064507-5016PR01, respectively); U.S. patentapplication Ser. No. 11/676,120, Filed Feb. 16, 2007 (Attorney DocketNo. 064507-5016US), which are herein incorporated by reference in theirentirety for all purposes. Methods of producing the compounds of theinvention are also described in these patent applications.

IIIe. Methods of Making the Compounds

The following exemplary schemes illustrate methods of preparingboron-containing molecules of the present invention. These methods arenot limited to producing the compounds shown, but can be used to preparea variety of molecules such as the compounds and complexes describedherein. The compounds of the present invention can also be synthesizedby methods not explicitly illustrated in the schemes but are well withinthe skill of one in the art. The compounds can be prepared using readilyavailable materials of known intermediates.

The compounds of the invention can be produced according to thestrategies described herein. Strategy A is described below for theproduction of 5-disubstituted phenoxy (halosubstituted)benzoxaborolederivatives:

Strategy A:

Step 1: The formyl group of compound 1 was protected as ethylene acetalwith ethylene glycol in the presence of acid catalyst. Ethylene glycolwas used in excess, typically from about 2 to about 10 equivalents tocompound 1. As for the acid catalysts, sulfonic acids, such aspara-toluene sulfonic acid or methanesulfonic acid, hydrogen chloride,hydrogen bromide, and the like are used at from about 1 to about 10 mol%. As for the solvent, toluene, benzene, xylene are used. The reactionis carried out under azetropic condition with a Dean-Stark head atreflux. The reaction is typically complete in from about 1 to about 24hours. This step may not be needed depending the reactivity of compound2.

Step 2: Compounds 2 and 3 are coupled in the presence of a base to give4. As for the base, carbonates, such as potassium carbonate, cesiumcarbonate, and sodium carbonate, sodium hydride, potassiumtert-butoxide, and the like are used. The amount is between from about 1to about 5 equivalent. Useful solvents include N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, and the like.The reaction is carried out at from about 70 to about 150° C. andcompleted in from about 1 to about 24 hours.

Step 3: Compound 4 is treated with acid to hydrolyze the acetal. Usefulacids include hydrochloric acid, hydrobromic acid, para-toluenesulfonicacid, methansulfonic acid, acetic acid, and the like in amounts of fromabout 1 to about 50 equivalents. Useful solvents include methanol,ethanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and thelike. The reaction is carried out at room temperature to reflux. Thereaction is complete in from about 1 to about 24 hours.

Step 4: Compound 5 is subjected to Miyaura coupling to introduce boronatom. A mixture of compounds 5, 6,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane, and potassium carbonate in a solvent is stirred atabout 50° C. to reflux. The solvent is chosen from 1,4-dioxane,1,2-dimethoxyethane, tetrahydrofuran, dimethylsulfoxide,dimethylformamide, toluene, and the like. The palladium catalyst is usedat from about 1 to about 5 mol %, and the base is used from about 2 toabout 5 equivalent. The reaction is completed in from about 1 to about24 hours.

Step 5: Compound 7 is treated with a reducing agent, such as sodiumborohydride and lithium aluminum hydride, in an inert solvent. Reducingagent is used from about 0.5 to about 2 equivalent. Inert solvent ismethanol, ethanol, tetrahydrofuran, ether, and the like. The reaction iscarried out at about 0° C. to room temperature, and complete in fromabout 1 to about 12 hours. Pinacol is removed by washing with aqueousboric acid during the extraction, treating crude product with water, orby freeze drying after purification.

Some 2-alkoxy-6-chloronicotinonitriles (2a) are prepared as follows:

Step 6: 2,6-Dichloronicotinic acid (8) is converted into correspondingacid chloride using oxalyl chloride or thionyl chloride in inertsolvent. As for the solvent, dichloromethane, 1,2-dichloroethane,tetrahydrofuran, are used. The reaction is carried out at about 0° C. toreflux, and completes in from about 1 to about 24 hours. Small amount ofN,N-dimethylformamide can be added to accelerate the reaction. The acidchloride formed is treated with ammonia to give compound 8.

Step 7: Compound 10 is obtained by treating 8 with correspondingalkoxide. As for the alkoxide, commercially available sodium methoxideor sodium ethoxide can be used. Otherwise, it is prepared in situ fromalcohol (ROH) and a base, such as sodium, sodium hydride, potassiumhydride, butyllithium, and the like. As for the solvent,tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide,1,2-dimethoxyethane, toluene, and the like are used. The reaction iscarried out at about 0° C. to room temperature for from about 1 to about24 hours.

Step 8: Compound 10 is treated with phosphorous oxychloride and pyridineto give 2a. Phosphorous oxychloride and pyridine are used in about 3 toabout 6 equivalent. The solvent is chosen from acetonitrile,tetrahydrofuran, toluene, and the like The reaction is carried out atroom temperature to reflux and complete in from about 1 to about 24hours.

Some 2-alkoxy-6-chloronicotinonitriles (2a) and6-alkoxy-2-chloronicotinonitriles (2b) are alternatively prepared asfollows:

Compounds 2a and 2b are obtained in the same condition as describedabove for step 7 from 2,6-dichloronicotinonitrile (11). The mixture canbe separated by silica gel column chromatography, preparative thin layerchromatography or high performance liquid chromatography.

Some 2-amino-6-chloronicotinonitrile derivatives (2c) and6-amino-2-chloronicotinonitrile derivatives (2d) are alternativelyprepared as follows:

Step 9: Compounds 2c and 2d are obtained by treating 11 withcorresponding amines with or without a base. Amine is used from about 1to about 10 equivalent. The base includes potassium carbonate, sodiumcarbonate, cesium carbonate, sodium hydride, potassium hydride,butyllithium, and the like. As for the solvent, tetrahydrofuran,1,4-dioxane, N,N-dimethylformamide, 1,2-dimethoxyethane, toluene, andthe like are used. The reaction is carried out at about 0° C. to refluxfor from about 1 to about 24 hours. The mixture can be separated bysilica gel column chromatography, preparative thin layer chromatographyor high performance liquid chromatography.

Compounds 1a and 1b are prepared as follows.

Step 10: (a) Compound 12 or 13 are treated with boron tribromide indichloromethane. Boron tribromide is used from about 1 to about 3equivalents. The reaction is carried out at about −78° C. to roomtemperature and complete in from about 1 to about 24 hours. (b)Alternatively, compound 12 or 13 are treated with 48% hydrobromic acidin acetic acid at from about 30 to about 100° C. for from about 6 toabout 72 hours.

Strategy B is described below for the production of mono- ordisubstituted 5-phenoxy derivatives:

Strategy B:

Strategy C is described below for the production of 5-phenoxyderivatives:

Strategy C:

Reagents and conditions: (a) ethylene glycol, p-TsOH, toluene, reflux, 6h; (b) K₂CO₃, DMF, 100° C., overnight; (c) 3 M HCl, THF, reflux, 2 h;(d) NaBH₄, MeOH, rt, 1 h; (e) 3,4-dihydro-2H-pyran, camphorsulfonicacid, CH₂Cl₂, rt, 2 h; (f) (i-PrO)₃B, n-BuLi, THF, −78° C. to rt, 3 h;(g) 6 M HCl, THF, rt, 3 h; (h) 6 M NaOH, MeOH, 1,4-dioxane, reflux, 6days; (i) EDCI, HOBt, DMAP, DMF, rt, overnight.

5-Phenoxybenzoxaborole derivatives were synthesized as shown above.Diaryl ether scaffold was made by nucleophilic aromatic substitutionreaction. The formyl group of compound 2 was protected as an acetal toavoid self condensation of 2. The formyl group of 4 was reduced toalcohol and protected as THP ether. The boron atom was then introducedby halogen-metal exchange with n-BuLi in the presence of triisopropylborate, which is known as the in-situ quench protocol (Li, W., et al. J.Org. Chem. 2002, 67, 5394-5397. Upon deprotection of THP group by HCl,the resulting hydroxymethyl group spontaneously cyclized to afford thedesired oxaborole.

Strategy D is described below for the production of carboxymonosubstituted 5-phenoxy derivatives:

Strategy D:

Reagents and conditions: 6 M NaOH, MeOH, 1,4-dioxane, reflux, 6 days.The carboxy derivative was obtained by the base hydrolysis of thecorresponding cyano compound.

Strategy E is described below for the production of amidemonosubstituted 5-phenoxy derivatives:

Strategy E:

Reagents and conditions: EDCI, HOBt, DMAP, DMF, rt, overnight. Amidederivatives were synthesized from the carboxy derivative using regularEDC/HOBt conditions.

Strategy F is described below for the production of estermonosubstituted 5-phenoxy derivatives:

Strategy F:

Step 11: Reagents and conditions: (a) ROH, sulfuric acid (1 to 10 mol%), reflux 1 to 24 hours or (b) RX (X=Cl, Br, I), base (potassiumcarbonate, sodium carbonate, sodium hydride, and the like), solvent(acetone, tetrahydrofuran, N,N-dimethylformamide, and the like), 0° C.to reflux, 1 to 24 hours.

Various 4-cyanophenoxy derivatives are synthesized as shown in StrategyG in similar ways to make compounds [I].

Strategy G:

Reagents and conditions: (a) ethylene glycol, p-TsOH, toluene, reflux, 6h; (b) K₂CO₃, DMF, 100° C., overnight; (c) 3 M HCl, THF, reflux, 2 h;(d) NaBH₄, MeOH, rt, 1 h; (e) 3,4-dihydro-2H-pyran, camphorsulfonicacid, CH₂Cl₂, rt, 2 h; (f) (i-PrO)₃B, n-BuLi, THF, −78° C. to rt, 3 h.

Carbamoyl substituted derivatives are prepared as follows:

Strategy H:

These compounds are prepared from compounds 19 and 3 in a similar mannerto Strategy A.

Aminomethyl substituted derivatives are prepared as follows:

Strategy I

These compounds are prepared by hydrogenation of corresponding cyanoderivatives. Typical condition is using palladium on charcoal (5 to 10%)in ethanol, methanol, ethyl acetate, and the like, at room temperatureto reflux at atmosphere pressure to about 50 psi for from about 1 toabout 72 hours. Alternatively, these compounds are prepared by lithiumaluminum hydride reduction in ether or tetrahydrofuran at about 0° C. toreflux for from about 1 to about 24 hours.

Alkylaminomethyl Derivatives are Prepared as Follows: Strategy J

Those compounds are prepared by regular reductive alkylation. As for thereducing agent, sodium borohydride or sodium cyanoborohydride istypically used. As for the solvent, methanol, ethanol, tetrahydrofuran,1,4-dioxane, and the like are used. The reaction is carried out at fromabout 0 to about 50° C. and complete in from about 1 to about 24 hours.

Sulfonylaminomethyl derivatives are prepared as follows:

Strategy K

These compounds are prepared by regular sulfonylation. The amine istreated with 1 to 10 equivalent of sulfonyl chloride. As for the base,triethylamine, diisopropylethylamine, DBU, pyridine,4-N,N-dimethylaminopyridine, sodium hydride, butyllithium, and the likeare used. As for the solvents, dichloromethane, 1,2-dichloroethane,tetrahydrofuran, acetonitrile, N,N-dimethylformamide, and the like areused. The reaction is carried out at from about 0 to about 50° C. andcomplete in from about 1 to about 24 hours.

Alkanoylaminomethyl derivatives are prepared as follows:

Strategy L

These compounds are prepared in a similar manner to Strategy K usingacid chloride instead of sulfonyl chloride.

Urea derivatives are prepared as follows:

Strategy M

These compounds are prepared by treating the amine with 1 to 10equivalent of corresponding isocyanate. As for the solvent,dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile,N,N-dimethylformamide, and the like are used. The reaction is carriedout at from about 0 to about 80° C. and complete in from about 1 toabout 24 hours.

Alternatively, urea derivatives are prepared as follows:

Strategy N

These compounds are prepared in a similar manner to Strategy K usingcarbamoyl chloride instead of sulfonyl chloride.

5-Alkoxy derivatives are prepared as follows:

Strategy P

These compounds are prepared from 5-hydroxy derivative by regularalkylation with from about 1 to about 10 equivalent of alkyl halide (RX)and a base. As for the base, potassium carbonate, sodium carbonate,cesium carbonate, sodium hydride, potassium tert-butoxide, and the likeare used. As for the solvent, acetone, acetonitrile, tetrahydrofuran,dichloromethane, N,N-dimethylformamide, and the like are used. Thereaction is carried out at from about 0 to about 100° C. and complete infrom about 1 to about 24 hours.

5-alkanoyloxy and 5-acryloyloxy derivatives are prepared as follows:

Strategy Q

These compounds are prepared in a similar manner to Strategy L.

The compounds of the invention can be converted into hydrates andsolvates by methods similar to those described herein.

III.f) Combinations Comprising Additional Therapeutic Agents

The compounds of the invention may also be used in combination withadditional therapeutic agents. The invention thus provides, in a furtheraspect, a combination comprising a compound described herein or apharmaceutically acceptable salt thereof together with at least oneadditional therapeutic agent. In an exemplary embodiment, the additionaltherapeutic agent is a compound of the invention. In an exemplaryembodiment, the additional therapeutic agent includes a boron atom. Inan exemplary embodiment, the additional therapeutic agent does notcontain a boron atom. In an exemplary embodiment, the additionaltherapeutic agent is a compound described in sections III a)-e).

When a compound of the invention is used in combination with a secondtherapeutic agent active against the same disease state, the dose ofeach compound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart. It will be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated and the age and the condition of the patient andwill be ultimately at the discretion of the attendant physician orveterinarian. In an exemplary embodiment, the additional therapeuticagent is an antiflammatory. In an exemplary embodiment, the additionaltherapeutic agent is a steroid or cyclosporine or psoralen or UVA orretinoid or methotrexete or vitamin D₃ analog. In an exemplaryembodiment, the steroid is a systemic steroid or a topical steroid. Inan exemplary embodiment, the additional therapeutic agent is topicalsteroid or antihistamine or calcineurin inhibitor. In an exemplaryembodiment, the additional therapeutic agent is CC-10004 or AWD-12-281.In an exemplary embodiment, the additional therapeutic agent is acorticosteroid or a NSAIDs. In an exemplary embodiment, the additionaltherapeutic agent is a PDE4 inhibitor. In an exemplary embodiment, theadditional therapeutic agent is rolipram or roflumilast.

The individual components of such combinations may be administeredeither simultaneously or sequentially in a unit dosage form. The unitdosage form may be a single or multiple unit dosage forms. In anexemplary embodiment, the invention provides a combination in a singleunit dosage form. An example of a single unit dosage form is a capsulewherein both the compound of the invention and the additionaltherapeutic agent are contained within the same capsule. In an exemplaryembodiment, the invention provides a combination in a two unit dosageform. An example of a two unit dosage form is a first capsule whichcontains the compound of the invention and a second capsule whichcontains the additional therapeutic agent. Thus the term ‘single unit’or ‘two unit’ or ‘multiple unit’ refers to the object which the patientingests, not to the interior components of the object. Appropriate dosesof known therapeutic agents will be readily appreciated by those skilledin the art.

The combinations referred to herein may conveniently be presented foruse in the form of a pharmaceutical formulation. Thus, an exemplaryembodiment of the invention is a pharmaceutical formulation comprisinga) a compound of the invention; b) an additional therapeutic agent andc) a pharmaceutically acceptable excipient. In an exemplary embodiment,the pharmaceutical formulation is a unit dosage form. In an exemplaryembodiment, the pharmaceutical formulation is a single unit dosage form.In an exemplary embodiment, the pharmaceutical formulation is a two unitdosage form. In an exemplary embodiment, the pharmaceutical formulationis a two unit dosage form comprising a first unit dosage form and asecond unit dosage form, wherein the first unit dosage form includes a)a compound of the invention and b) a first pharmaceutically acceptableexcipient; and the second unit dosage form includes c) an additionaltherapeutic agent and d) a second pharmaceutically acceptable excipient.

IV. The Methods

a) Decreasing the Production of a Cytokine and/or Chemokine

In another aspect, the invention provides a method for decreasing theproduction of a cytokine and/or a chemokine, the method comprising:contacting a cell with a compound of the invention, wherein productionof the cytokine and/or chemokine by the cell is decreased. In anotheraspect, the invention provides a method for decreasing the production ofa cytokine and/or a chemokine, the method comprising: contacting a cellwith a compound described herein or a pharmaceutically acceptable saltthereof, wherein production of the cytokine and/or chemokine by the cellis decreased. In an exemplary embodiment, the compound of the inventionis a compound described herein, or a pharmaceutically acceptable saltthereof. In an exemplary embodiment, the compound of the invention is acompound described herein. In an exemplary embodiment, the cell iscontacted with a therapeutically effective amount of the compound. In anexemplary embodiment, the compound is according to a formula describedherein. In an exemplary embodiment, the compound is a member selectedfrom C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15,C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29,C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43,C44, C45, C46, C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57,C58, C59, C60, C61, C62, C63, C64, C65, C66, C67, C68, C69, C70, C71,C72, C73, C74, C75, C76, C77, C78, C79, C80, C81, C82, C83, C84, C85,C86, C87, C88, C89, C90, C91, C92, C93, C94, C95, C96, C97, C98, C99 andC100. In an exemplary embodiment, the compound is a member selected fromD1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16,D17, D18, D19, D20, D21, D22, D23, D24, D25, D26, D27, D28, D29, D30,D31, D32, D33, D34, D35, D36, D37, D38, D39, D40, D41, D42, D43, D44,D45, D46, D47, D48, D49, D50, D51, D52, D53, D54, D55, D56, D57, D58,D59, D60, D61, D62, D63, D64, D65, D66, D67, D68, D69, D70, D71, D72,D73, D74, D75, D76, D77, D78, D79, D80, D81, D82, D83, D84, D85, D86,D87, D88, D89, D90, D91, D92, D93, D94, D95, D96, D97, D98, D99, D100,D101, D102, D103, D104, D105, D106, D107, D108, D109, D110, D111, D112,D113, D114, D115, D116, D117, D118, D119, D120, D121, D122, D123, D124,D125, D126, D127, D128, D129, D130, D131, D132, D133, D134, D135, D136,D137, D138, D139, D140, D141, D142, D143, D144, D145, D146, D147, D148,D149, D150, D151, D152, D153, D154, D155, D156, D157, D158, D159, D160,D161, D162, D163, D164, D165, D166, D167, D168, D169, D170, D171, D172,D173, D174, D175, D176, D177, D178, D179, D180, D181, D182, D183, D184,D185, D186, D187, D188, D189, D190, D191, D192, D193, D194, D195, D196,D197, D198, D199, D200, D201, D202, D203, D204, D205, D206, D207, D208,D209, D210, D211, D212, D213, D214, D215, D216, D217, D218, D219, D220,D221, D222, D223, D224, D225, D226, D227, D228 and D229. In an exemplaryembodiment, the compound is C17. In another exemplary embodiment, thecompound is C27. In another exemplary embodiment, the compound is C23 orC24. In another exemplary embodiment, the compound is C25. In anotherexemplary embodiment, the compound is C26. In another exemplaryembodiment, the compound is C37. In an exemplary embodiment, thecompound is a member selected from D46, D86, D99, D100, D107, D108,D114, D122, D125, D126, D127, D128, D131, D140 and D141, and saltsthereof. In an exemplary embodiment, the compound is a member selectedfrom D95, D96, D97, D102, D110, D111, D113, D115, D121, D129, D130,D132, and salts thereof. In an exemplary embodiment, the compound is amember selected from D47, D109, D116, D118, D119, D120, D123, and saltsthereof. In an exemplary embodiment, the compound is a member selectedfrom D98, D101, D106, and salts thereof. In an exemplary embodiment, thecompound is a member selected from D11, D12, D37, D38, D39, D40, D41,D42, D43, D124, D142, D143, D146, and salts thereof. In an exemplaryembodiment, the compound is a member selected from D14, D15, D16, D17,D28, D29, D30, D31, D133, D134, D135, D144, D145, D147, and saltsthereof.

In an exemplary embodiment, the method is for decreasing the productionof a cytokine, which is a TH1 cytokine. In an exemplary embodiment, theTH1 cytokine is a member selected from IFN-γ and IL-2.

In an exemplary embodiment, the method is for decreasing the productionof a cytokine, which is a TH2 cytokine. In an exemplary embodiment, theTH2 cytokine is a member selected from IL-4, IL-5 and IL-10.

In an exemplary embodiment, the method is for decreasing the productionof a cytokine, which is a member selected from IL-1α, IL-1β, IL-2, IL-3,IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, IL-23, TNF-α, LT, LIF,Oncostatin, IFNα, IFNβ and IFN-γ. In another exemplary embodiment, thecytokine is a member selected from IL-1β, IL-2, IL-3, IL-6, IL-7, IL-9,IL-12, IL-23, TNF-α, LT, LIF, Oncostatin, and IFN-γ. In anotherexemplary embodiment, the cytokine is a member selected from IL-1β,IL-2, IL-23, TNF-α and IFN-γ. In another exemplary embodiment, thecytokine is TNF-α.

In an exemplary embodiment, the method is for decreasing the release ofa cytokine, which is a member selected from IL-1β, IL-2, IL-4, IL-5,IL-6, IL-8, IL-10, IL-12, IL-23, TNF-α and IFN-γ.

In an exemplary embodiment, the method is for decreasing the productionof a cytokine, which is a member selected from IL-4, IL-10, IL-11, W-13and TGF-β.

In an exemplary embodiment, the method is for decreasing the productionof a chemokine, which is a member selected from IL-8, Gro-α, MIP-1,MCP-1, PGE2, ENA-78, and RANTES. In an exemplary embodiment, thechemokine is a member selected from MCP-1 and PGE2.

In an exemplary embodiment, for any of the methods described herein, thecompound of the invention is present in an amount which will inhibit theproduction of a cytokine and/or a chemokine by at least about 5 to about100%, or at least about 30 to about 100%, 40 to about 100%, or at leastabout 50 to about 100%, or at least about 60 to about 100%, or at leastabout 70 to about 100%, or at least about 80 to about 100%, or at leastabout 90 to about 100%, or at least about 30 to about 70%, or at leastabout 40 to about 90%, or at least about 45 to about 80%, or at leastabout 55 to about 75%, or at least about 75 to about 98%, or at leastabout 55 to about 99%, or at least about 5% to about 20% or at leastabout 10% to about 25%. In an exemplary embodiment, the compound of theinvention is a compound described herein.

b) Increasing the Production of a Cytokine and/or a Chemokine

In another aspect, the invention provides a method for increasing theproduction of a cytokine and/or a chemokine, the method comprising:contacting a cell with a compound of the invention, wherein productionof the cytokine and/or chemokine by the cell is increased. In anexemplary embodiment, the compound is described herein or apharmaceutically acceptable salt thereof. In an exemplary embodiment,the compound of the invention is a compound described herein. In anexemplary embodiment, the cell is contacted with a therapeuticallyeffective amount of the compound. In an exemplary embodiment, thecompound is according to a formula described herein. In an exemplaryembodiment, the compound is a member selected from C1, C2, C3, C4, C5,C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20,C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34,C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48,C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62,C63, C64, C65, C66, C67, C68, C69, C70, C71, C72, C73, C74, C75, C76,C77, C78, C79, C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C90,C91, C92, C93, C94, C95, C96, C97, C98, C99 and C100. In an exemplaryembodiment, the compound is a member selected from D1, D2, D3, D4, D5,D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16, D17, D18, D19, D20,D21, D22, D23, D24, D25, D26, D27, D28, D29, D30, D31, D32, D33, D34,D35, D36, D37, D38, D39, D40, D41, D42, D43, D44, D45, D46, D47, D48,D49, D50, D51, D52, D53, D54, D55, D56, D57, D58, D59, D60, D61, D62,D63, D64, D65, D66, D67, D68, D69, D70, D71, D72, D73, D74, D75, D76,D77, D78, D79, D80, D81, D82, D83, D84, D85, D86, D87, D88, D89, D90,D91, D92, D93, D94, D95, D96, D97, D98, D99, D100, D101, D102, D103,D104, D105, D106, D107, D108, D109, D110, D111, D112, D113, D114, D115,D116, D117, D118, D119, D120, D121, D122, D123, D124, D125, D126, D127,D128, D129, D130, D131, D132, D133, D134, D135, D136, D137, D138, D139,D140, D141, D142, D143, D144, D145, D146, D147, D148, D149, D150, D151,D152, D153, D154, D155, D156, D157, D158, D159, D160, D161, D162, D163,D164, D165, D166, D167, D168, D169, D170, D171, D172, D173, D174, D175,D176, D177, D178, D179, D180, D181, D182, D183, D184, D185, D186, D187,D188, D189, D190, D191, D192, D193, D194, D195, D196, D197, D198, D199,D200, D201, D202, D203, D204, D205, D206, D207, D208, D209, D210, D211,D212, D213, D214, D215, D216, D217, D218, D219, D220, D221, D222, D223,D224, D225, D226, D227, D228 and D229. In an exemplary embodiment, thecompound is C17. In another exemplary embodiment, the compound is C27.In another exemplary embodiment, the compound is C23 or C24. In anotherexemplary embodiment, the compound is C26.

In an exemplary embodiment, the method is for increasing the productionof a cytokine, which is a TH1 cytokine. In an exemplary embodiment, theTH1 cytokine is a member selected from IFN-γ and IL-2.

In an exemplary embodiment, the method is for increasing the productionof a cytokine, which is a TH2 cytokine. In an exemplary embodiment, theTH2 cytokine is a member selected from IL-4, IL-5 and IL-10.

In an exemplary embodiment, the method is for increasing the productionof a cytokine, which is a member selected from IL-4, IL-10, IL-11, W-13and TGF-β.

In an exemplary embodiment, the method is for increasing the productionof a chemokine, which is a member selected from IL-8, Gro-α, MIP-1,MCP-1, PGE2, ENA-78, and RANTES. In an exemplary embodiment, thechemokine is a member selected from MCP-1 and PGE2.

In an exemplary embodiment, for any of the methods described herein, thecompound of the invention is present in an amount which will increasethe production of a cytokine and/or a chemokine by at least about 5 toabout 100%, or at least about 30 to about 100%, 40 to about 100%, or atleast about 50 to about 100%, or at least about 60 to about 100%, or atleast about 70 to about 100%, or at least about 80 to about 100%, or atleast about 90 to about 100%, or at least about 30 to about 70%, or atleast about 40 to about 90%, or at least about 45 to about 80%, or atleast about 55 to about 75%, or at least about 75 to about 98%, or atleast about 55 to about 99%, or at least about 5% to about 20% or atleast about 10% to about 25%. In an exemplary embodiment, the compoundof the invention is a compound described herein.

c) Decreasing the Release of a Cytokine and/or Chemokine

In another aspect, the invention provides a method for decreasing therelease of a cytokine and/or a chemokine, the method comprising:contacting a cell with a compound of the invention, wherein the releaseof the cytokine and/or chemokine by the cell is decreased. In anexemplary embodiment, the compound of the invention is a compounddescribed herein or a pharmaceutically acceptable salt thereof. Thecompound of the invention is a compound described herein. In anexemplary embodiment, the cell is contacted with a therapeuticallyeffective amount of the compound. In an exemplary embodiment, thecompound is according to a formula described herein. In an exemplaryembodiment, the compound is a member selected from C1, C2, C3, C4, C5,C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20,C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34,C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48,C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62,C63, C64, C65, C66, C67, C68, C69, C70, C71, C72, C73, C74, C75, C76,C77, C78, C79, C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C90,C91, C92, C93, C94, C95, C96, C97, C98, C99 and C100. In an exemplaryembodiment, the compound is a member selected from D1, D2, D3, D4, D5,D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16, D17, D18, D19, D20,D21, D22, D23, D24, D25, D26, D27, D28, D29, D30, D31, D32, D33, D34,D35, D36, D37, D38, D39, D40, D41, D42, D43, D44, D45, D46, D47, D48,D49, D50, D51, D52, D53, D54, D55, D56, D57, D58, D59, D60, D61, D62,D63, D64, D65, D66, D67, D68, D69, D70, D71, D72, D73, D74, D75, D76,D77, D78, D79, D80, D81, D82, D83, D84, D85, D86, D87, D88, D89, D90,D91, D92, D93, D94, D95, D96, D97, D98, D99, D100, D101, D102, D103,D104, D105, D106, D107, D108, D109, D100, D111, D112, D113, D114, D115,D116, D117, D118, D119, D120, D121, D122, D123, D124, D125, D126, D127,D128, D129, D130, D131, D132, D133, D134, D135, D136, D137, D138, D139,D140, D141, D142, D143, D144, D145, D146, D147, D148, D149, D150, D151,D152, D153, D154, D155, D156, D157, D158, D159, D160, D161, D162, D163,D164, D165, D166, D167, D168, D169, D170, D171, D172, D173, D174, D175,D176, D177, D178, D179, D180, D181, D182, D183, D184, D185, D186, D187,D188, D189, D190, D191, D192, D193, D194, D195, D196, D197, D198, D199,D200, D201, D202, D203, D204, D205, D206, D207, D208, D209, D210, D211,D212, D213, D214, D215, D216, D217, D218, D219, D220, D221, D222, D223,D224, D225, D226, D227, D228 and D229. In an exemplary embodiment, thecompound is C17. In another exemplary embodiment, the compound is C27.In another exemplary embodiment, the compound is C23 or C24. In anotherexemplary embodiment, the compound is C25. In another exemplaryembodiment, the compound is C26. In another exemplary embodiment, thecompound is C37. In an exemplary embodiment, the compound is a memberselected from D46, D86, D99, D100, D107, D108, D114, D122, D125, D126,D127, D128, D131, D140 and D141, and salts thereof. In an exemplaryembodiment, the compound is a member selected from D95, D96, D97, D102,D110, D111, D113, D115, D121, D129, D130, D132, and salts thereof. In anexemplary embodiment, the compound is a member selected from D47, D109,D116, D118, D119, D120, D123, and salts thereof. In an exemplaryembodiment, the compound is a member selected from D98, D101, D106, andsalts thereof. In an exemplary embodiment, the compound is a memberselected from D11, D12, D37, D38, D39, D40, D41, D42, D43, D124, D142,D143, D146, and salts thereof. In an exemplary embodiment, the compoundis a member selected from D14, D15, D16, D17, D28, D29, D30, D31, D133,D134, D135, D144, D145, D147, and salts thereof.

In an exemplary embodiment, the method is for decreasing the release ofa cytokine, which is a TH1 cytokine. In an exemplary embodiment, the TH1cytokine is a member selected from IFN-γ and IL-2.

In an exemplary embodiment, the method is for decreasing the release ofa cytokine, which is a TH2 cytokine. In an exemplary embodiment, the TH2cytokine is a member selected from IL-4, IL-5 and IL-10.

In an exemplary embodiment, the method is for decreasing the release ofa cytokine, which is a member selected from IL-1α, IL-1β, IL-2, IL-3,IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, IL-23, TNF-α, LT, LIF,Oncostatin, IFNα, IFNβ and IFN-γ. In another exemplary embodiment, thecytokine is a member selected from IL-1β, IL-2, IL-3, IL-6, IL-7, IL-9,IL-12, IL-23, TNF-α, LT, LIF, Oncostatin, and IFN-γ. In anotherexemplary embodiment, the cytokine is a member selected from IL-1β,IL-2, IL-23, TNF-α and IFN-γ. In another exemplary embodiment, thecytokine is TNF-α. In another exemplary embodiment, the cytokine isIFN-γ.

In an exemplary embodiment, the method is for decreasing the release ofa cytokine, which is a member selected from IL-1β, IL-2, IL-4, IL-5,IL-6, IL-8, IL-10, IL-12, IL-23, TNF-α and IFN-γ.

In an exemplary embodiment, the compound of the invention decreases therelease of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-23,TNF-α and IFN-γ. In an exemplary embodiment, the compound is C17.

In an exemplary embodiment, the method is for decreasing the release ofa cytokine, which is a member selected from IL-4, IL-10, IL-11, W-13 andTGF-β.

In an exemplary embodiment, the method is for decreasing the release ofa chemokine, which is a member selected from IL-8, Gro-α, MIP-1, MCP-1,PGE2, ENA-78, and RANTES. In an exemplary embodiment, the chemokine is amember selected from MCP-1 and PGE2. In an exemplary embodiment, thecompound is C17 and the chemokine is a member selected from MCP-1 andPGE2.

In an exemplary embodiment, the compound of the invention decreases therelease of TNF-α, IL-2, IFNγ, IL-5, and IL-10. In an exemplaryembodiment, the compound of the invention does not substantiallydecrease the release of IL-1β, IL-6 and IL-8. In an exemplaryembodiment, the compound of the invention does not substantiallydecrease the release of IL-1β. In an exemplary embodiment, the compoundof the invention does not substantially decrease the release of IL-4. Inan exemplary embodiment, the compound decreases the release of IL-12 andIL-23. In an exemplary embodiment, the compound is C27.

In an exemplary embodiment, for any of the methods described herein, thecompound of the invention is present in an amount which will decreasethe release of a cytokine and/or a chemokine by at least about 5 toabout 100%, or at least about 30 to about 100%, 40 to about 100%, or atleast about 50 to about 100%, or at least about 60 to about 100%, or atleast about 70 to about 100%, or at least about 80 to about 100%, or atleast about 90 to about 100%, or at least about 30 to about 70%, or atleast about 40 to about 90%, or at least about 45 to about 80%, or atleast about 55 to about 75%, or at least about 75 to about 98%, or atleast about 55 to about 99%, or at least about 5% to about 20% or atleast about 10% to about 25%. In another exemplary embodiment, thecompound of the invention is a compound described herein or apharmaceutically acceptable salt thereof.

d) Increasing the Release of a Cytokine and/or a Chemokine

In another aspect, the invention provides a method for increasing theproduction of a cytokine and/or a chemokine, the method comprising:contacting a cell with a compound of the invention, wherein release ofthe cytokine and/or chemokine by the cell is increased. In an exemplaryembodiment, the compound of the invention is a compound described hereinor a pharmaceutically acceptable salt thereof. In an exemplaryembodiment, the compound is described herein. In an exemplaryembodiment, the cell is contacted with a therapeutically effectiveamount of the compound. In an exemplary embodiment, the compound isaccording to a formula described herein. In an exemplary embodiment, thecompound is a member selected from C1, C2, C3, C4, C5, C6, C7, C8, C9,C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23,C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37,C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51,C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65,C66, C67, C68, C69, C70, C71, C72, C73, C74, C75, C76, C77, C78, C79,C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C90, C91, C92, C93,C94, C95 and C96. In an exemplary embodiment, the compound is a memberselected from D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12, D13,D14, D15, D16, D17, D18, D19, D20, D21, D22, D23, D24, D25, D26, D27,D28, D29, D30, D31, D32, D33, D34, D35, D36, D37, D38, D39, D40, D41,D42, D43, D44, D45, D46, D47, D48, D49, D50, D51, D52, D53, D54, D55,D56, D57, D58, D59, D60, D61, D62, D63, D64, D65, D66, D67, D68, D69,D70, D71, D72, D73, D74, D75, D76, D77, D78, D79, D80, D81, D82, D83,D84, D85, D86, D87, D88, D89, D90, D91, D92, D93, D94, D95, D96, D97,D98, D99, D100, D101, D102, D103, D104, D105, D106, D107, D108, D109,D110, D111, D112, D113, D114, D115, D116, D117, D118, D119, D120, D121,D122, D123, D124, D125, D126, D127, D128, D129, D130, D131, D132, D133,D134, D135, D136, D137, D138, D139, D140, D141, D142, D143, D144, D145,D146, D147, D148, D149, D150, D151, D152, D153, D154, D155, D156, D157,D158, D159, D160, D161, D162, D163, D164, D165, D166, D167, D168, D169,D170, D171, D172, D173, D174, D175, D176, D177, D178, D179, D180, D181,D182, D183, D184, D185, D186, D187, D188, D189, D190, D191, D192, D193,D194, D195, D196, D197, D198, D199, D200, D201, D202, D203, D204, D205,D206, D207, D208, D209, D210, D211, D212, D213, D214, D215, D216, D217,D218, D219, D220, D221, D222, D223, D224, D225, D226, D227, D228 andD229. In an exemplary embodiment, the compound is C17. In anotherexemplary embodiment, the compound is C27. In another exemplaryembodiment, the compound is C23 or C24. In another exemplary embodiment,the compound is C26.

In an exemplary embodiment, the method is for increasing the release ofa cytokine, which is a TH1 cytokine. In an exemplary embodiment, the TH1cytokine is a member selected from IFN-γ and IL-2.

In an exemplary embodiment, the method is for increasing the release ofa cytokine, which is a TH2 cytokine. In an exemplary embodiment, the TH2cytokine is a member selected from IL-4, IL-5 and IL-10.

In an exemplary embodiment, the method is for increasing the release ofa cytokine, which is a member selected from IL-4, IL-10, IL-11, W-13 andTGF-β.

In an exemplary embodiment, the method is for increasing the release ofa chemokine, which is a member selected from IL-8, Gro-α, MIP-1, MCP-1,PGE2, ENA-78, and RANTES. In an exemplary embodiment, the chemokine is amember selected from MCP-1 and PGE2.

In an exemplary embodiment, for any of the methods described herein, thecompound of the invention is present in an amount which will increaserelease of a cytokine and/or a chemokine by at least about 5 to about100%, or at least about 30 to about 100%, 40 to about 100%, or at leastabout 50 to about 100%, or at least about 60 to about 100%, or at leastabout 70 to about 100%, or at least about 80 to about 100%, or at leastabout 90 to about 100%, or at least about 30 to about 70%, or at leastabout 40 to about 90%, or at least about 45 to about 80%, or at leastabout 55 to about 75%, or at least about 75 to about 98%, or at leastabout 55 to about 99%, or at least about 5% to about 20% or at leastabout 10% to about 25%. In an exemplary embodiment, the compound of theinvention is a compound described herein or a pharmaceuticallyacceptable salt thereof.

e) Inhibiting a Phosphodiesterase

In another aspect, the invention provides a method for inhibiting aphosphodiesterase (PDE), the method comprising: contacting thephosphodiesterase with a compound of the invention, wherein thephosphodiesterase is inhibited. In an exemplary embodiment, the compoundof the invention is a compound described herein or a pharmaceuticallyacceptable salt thereof. In an exemplary embodiment, the compound of theinvention is a compound described herein. In an exemplary embodiment,the amount of the compound is a therapeutically effective amount. In anexemplary embodiment, the compound is according to a formula describedherein. In an exemplary embodiment, the compound is according to thefollowing formula:

wherein B is boron. R¹ is a member selected from a negative charge, asalt counterion, H, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl. M isa member selected from oxygen, sulfur and NR². R² is a member selectedfrom H, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. J is a member selected from(CR³R⁴)_(n1) and CR⁵. R³, R⁴, and R⁵ are members independently selectedfrom H, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. n1 isan integer selected from 0 to 2. W is a member selected from C═O(carbonyl), (CR⁶R⁷)_(m1) and CR⁸. R⁶, R⁷, and R⁸ are membersindependently selected from H, cyano, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. m1 is an integer selected from 0 and 1. A is a memberselected from CR⁹ and N. D is a member selected from CR¹⁰ and N. E is amember selected from CR⁹¹ and N. G is a member selected from CR¹² and N.R⁹, R¹⁰, R¹¹ and R¹² are members independently selected from H, OR*,NR*R**, SR*, —S(O)R*, —S(O)₂R*, —S(O)₂NR*R**, —C(O)R*, —C(O)OR*,—C(O)NR*R**, nitro, halogen, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl,wherein each R* and R** are members independently selected from H,nitro, halogen, cyano, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. Thecombination of nitrogens (A+D+E+G) is an integer selected from 0 to 3. Amember selected from R³, R⁴ and R⁵ and a member selected from R⁶, R⁷ andR⁸, together with the atoms to which they are attached, are optionallyjoined to form a 4 to 7 membered ring. R³ and R⁴, together with theatoms to which they are attached, are optionally joined to form a 4 to 7membered ring. R⁶ and R⁷, together with the atoms to which they areattached, are optionally joined to form a 4 to 7 membered ring. R⁹ andR¹⁰, together with the atoms to which they are attached, are optionallyjoined to form a 4 to 7 membered ring. R¹⁰ and R¹¹, together with theatoms to which they are attached, are optionally joined to form a 4 to 7membered ring. R¹¹ and R¹², together with the atoms to which they areattached, are optionally joined to form a 4 to 7 membered ring.

In an exemplary embodiment, the compound is a member selected from C1,C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17,C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31,C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45,C46, C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59,C60, C61, C62, C63, C64, C65, C66, C67, C68, C69, C70, C71, C72, C73,C74, C75, C76, C77, C78, C79, C80, C81, C82, C83, C84, C85, C86, C87,C88, C89, C90, C91, C92, C93, C94, C95 and C96, or a pharmaceuticallyacceptable salt thereof. In an exemplary embodiment, the compound is amember selected from D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12,D13, D14, D15, D16, D17, D18, D19, D20, D21, D22, D23, D24, D25, D26,D27, D28, D29, D30, D31, D32, D33, D34, D35, D36, D37, D38, D39, D40,D41, D42, D43, D44, D45, D46, D47, D48, D49, D50, D51, D52, D53, D54,D55, D56, D57, D58, D59, D60, D61, D62, D63, D64, D65, D66, D67, D68,D69, D70, D71, D72, D73, D74, D75, D76, D77, D78, D79, D80, D81, D82,D83, D84, D85, D86, D87, D88, D89, D90, D91, D92, D93, D94, D95, D96,D97, D98, D99, D100, D101, D102, D103, D104, D105, D106, D107, D108,D109, D110, D111, D112, D113, D114, D115, D116, D117, D118, D119, D120,D121, D122, D123, D124, D125, D126, D127, D128, D129, D130, D131, D132,D133, D134, D135, D136, D137, D138, D139, D140, D141, D142, D143, D144,D145, D146, D147, D148, D149, D150, D151, D152, D153, D154, D155, D156,D157, D158, D159, D160, D161, D162, D163, D164, D165, D166, D167, D168,D169, D170, D171, D172, D173, D174, D175, D176, D177, D178, D179, D180,D181, D182, D183, D184, D185, D186, D187, D188, D189, D190, D191, D192,D193, D194, D195, D196, D197, D198, D199, D200, D201, D202, D203, D204,D205, D206, D207, D208, D209, D210, D211, D212, D213, D214, D215, D216,D217, D218, D219, D220, D221, D222, D223, D224, D225, D226, D227, D228and D229. In an exemplary embodiment, the compound is C17. In anotherexemplary embodiment, the compound is C27. In another exemplaryembodiment, the compound is C23. In another exemplary embodiment, thecompound is C24. In another exemplary embodiment, the compound is C25.In another exemplary embodiment, the compound is C26. In an exemplaryembodiment, the compound is a member selected from D46, D86, D99, D100,D107, D108, D114, D122, D125, D126, D127, D128, D131, D140 and D141, andsalts thereof. In an exemplary embodiment, the compound is a memberselected from D95, D96, D97, D102, D110, D111, D113, D115, D121, D129,D130, D132, and salts thereof. In an exemplary embodiment, the compoundis a member selected from D47, D109, D116, D118, D119, D120, D123, andsalts thereof. In an exemplary embodiment, the compound is a memberselected from D98, D101, D106, and salts thereof. In an exemplaryembodiment, the compound is a member selected from D11, D12, D37, D38,D39, D40, D41, D42, D43, D124, D142, D143, D146, and salts thereof. Inan exemplary embodiment, the compound is a member selected from D14,D15, D16, D17, D28, D29, D30, D31, D133, D134, D135, D144, D145, D147,and salts thereof.

In an exemplary embodiment, the compound is a member selected from5-(4-Cyanophenoxy)-1-hydroxy-2,1-benzoxaborole,1,3-Dihydro-1-hydroxy-5-phenoxy-2,1-benzoxaborole

5-(2-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

5-[4-(N,N-Diethylcarbamoyl)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

1,3-Dihydro-1-hydroxy-5-[4-(morpholinocarbonyl)phenoxy]-2,1-benzoxaborole

5-(3,4-Dicyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

1,3-Dihydro-1-hydroxy-5-(3-cyanophenoxy)-2,1-benzoxaborole

5-(4-Carboxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

5-(5-Cyanopyridin-2-yloxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

5-(4-Cyanobenzyloxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acidmethyl ester

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acidmethyl ester

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acidethyl ester

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acidpropyl ester

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acidisopropyl ester

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid2-dimethylamino-ethyl ester

N-Benzyl-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-N-(2-hydroxy-ethyl)-benzamide

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-N-pyridin-2-ylmethyl-benzamide

[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-(4-methyl-piperazin-1-yl)-methanone

1-{4-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoyl]-piperazin-1-yl}-ethanone

N-(2-Dimethylamino-ethyl)-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide

2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-pyrimidine-5-carboxylicacid methyl ester

2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-thiazole-4-carboxylicacid methyl ester

2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-thiazole-5-carboxylicacid methyl ester

5-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-pyridine-2-carboxylicacid ethyl ester

In an exemplary embodiment, the phosphodiesterase is a member selectedfrom PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10 andPDE11. In an exemplary embodiment, the phosphodiesterase is PDE4. In anexemplary embodiment, the PDE4 is a member selected from PDE4A, PDE4B,PDE4C and PDE4D. In an exemplary embodiment, the PDE4 is PDE4B. In anexemplary embodiment, the phosphodiesterase is PDE7.

In an exemplary embodiment, the invention provides a method forinhibiting a phosphodiesterase4 (PDE4), but not significantly inhibitingat least one PDE which is a member selected from PDE1, PDE2, PDE3, PDE5and PDE6, involving contacting a cell with a compound of the invention,thereby providing said inhibition. In an exemplary the compound is C27.

In another exemplary embodiment, the invention provides a method forinhibiting a phosphodiesterase4 (PDE4), the method comprising:contacting the phosphodiesterase with C17, or a pharmaceuticallyacceptable salt thereof, wherein the phosphodiesterase4 (PDE4) isinhibited. In another exemplary embodiment, the invention provides amethod for inhibiting a phosphodiesterase7 (PDE7), the methodcomprising: contacting the phosphodiesterase with C17, or apharmaceutically acceptable salt thereof, wherein the phosphodiesterase7(PDE7) is inhibited. In another exemplary embodiment, the inventionprovides a method for inhibiting a phosphodiesterase4 (PDE4), the methodcomprising: contacting the phosphodiesterase with C27, or apharmaceutically acceptable salt thereof, wherein the phosphodiesterase4(PDE4) is inhibited. In another exemplary embodiment, the inventionprovides a method for inhibiting a phosphodiesterase7 (PDE7), the methodcomprising: contacting the phosphodiesterase with C27, or apharmaceutically acceptable salt thereof, wherein the phosphodiesterase7(PDE7) is inhibited. In an exemplary embodiment, the amount of thecompound is a therapeutically effective amount.

In another exemplary embodiment, the invention provides a method forinhibiting a phosphodiesterase4 (PDE4), the method comprising:contacting the phosphodiesterase with C23 or C24 or C25, or apharmaceutically acceptable salt thereof, wherein the phosphodiesterase4(PDE4) is inhibited.

In another exemplary embodiment, the invention provides a method forinhibiting a phosphodiesterase4 (PDE4), the method comprising:contacting the phosphodiesterase with D46 or D86 or D99 or D100 or D107or D108 or D114 or D122 or D125 or D126 or D127 or D128 or D131 or D140and D141, or a pharmaceutically acceptable salt thereof, wherein thephosphodiesterase4 (PDE4) is inhibited.

In another exemplary embodiment, the invention provides a method forinhibiting a phosphodiesterase4 (PDE4), the method comprising:contacting the phosphodiesterase with D95 or D96 or D97 or D102 or D110or D111 or D113 or D115 or D121 or D129 or D130 or D132, and, or apharmaceutically acceptable salt thereof, wherein the phosphodiesterase4(PDE4) is inhibited.

In another exemplary embodiment, the invention provides a method forinhibiting a phosphodiesterase4 (PDE4), the method comprising:contacting the phosphodiesterase with D47 or D109 or D116 or D118 orD119 or D120 or D123, and, or a pharmaceutically acceptable saltthereof, wherein the phosphodiesterase4 (PDE4) is inhibited.

In another exemplary embodiment, the invention provides a method forinhibiting a phosphodiesterase4 (PDE4), the method comprising:contacting the phosphodiesterase with D98 or D101 or D106, and, or apharmaceutically acceptable salt thereof, wherein the phosphodiesterase4(PDE4) is inhibited.

In another exemplary embodiment, the invention provides a method forinhibiting a phosphodiesterase4 (PDE4), the method comprising:contacting the phosphodiesterase with D11 or D12 or D37 or D38 or D39 orD40 or D41 or D42 or D43 or D124 or D142 or D143 or D146, and, or apharmaceutically acceptable salt thereof, wherein the phosphodiesterase4(PDE4) is inhibited.

In another exemplary embodiment, the invention provides a method forinhibiting a phosphodiesterase4 (PDE4), the method comprising:contacting the phosphodiesterase with D14 or D15 or D16 or D17 or D28 orD29 or D30 or D31 or D133 or D134 or D135 or D144 or D145 or D147, and,or a pharmaceutically acceptable salt thereof, wherein thephosphodiesterase4 (PDE4) is inhibited.

In an exemplary embodiment, for any of the methods described herein, theof the invention, or a compound described by a formula presented herein,is present in an amount which will inhibit a phosphodiesterase describedherein by at least about 5 to about 100%, or at least about 30 to about100%, 40 to about 100%, or at least about 50 to about 100%, or at leastabout 60 to about 100%, or at least about 70 to about 100%, or at leastabout 80 to about 100%, or at least about 90 to about 100%, or at leastabout 30 to about 70%, or at least about 40 to about 90%, or at leastabout 45 to about 80%, or at least about 55 to about 75%, or at leastabout 75 to about 98%, or at least about 55 to about 99%, or at leastabout 5% to about 20% or at least about 10% to about 25%. In anexemplary embodiment, the compound of the invention is a compounddescribed herein or a pharmaceutically acceptable salt thereof.

f) Conditions and Effects

In another aspect, the invention provides a method of treating and/orpreventing a condition, and/or enhancing an effect, in an animal, themethod comprising administering to the animal an effective amount of acompound of the invention, thereby treating and/or preventing thecondition. In an exemplary embodiment, the compound of the invention isa compound described herein. In an exemplary embodiment, the compound ofthe invention is a pharmaceutically acceptable salt of a compounddescribed herein. In an exemplary embodiment, the effective amount is anamount effective to treat the condition. In an exemplary embodiment, theeffective amount is an amount effective to prevent the condition. In anexemplary embodiment, the animal is not otherwise is need of treatmentwith the compound of the invention. In an exemplary embodiment, thecompound is according to a formula described herein. In another aspect,the invention provides a method of treating a condition in an animal inneed of the treatment, the method comprising administering to the animalan amount of a compound of the invention, thereby treating thecondition. In another aspect, the invention provides a method oftreating a condition in an animal in need of the treatment, the methodcomprising administering to the animal a therapeutically effectiveamount of a compound of the invention, thereby treating the condition.In another aspect, the invention provides a method of preventing acondition, in an animal, the method comprising administering to theanimal an amount of a compound of the invention, thereby preventing thecondition. In another aspect, the invention provides a method ofenhancing an effect, in an animal, the method comprising administeringto the animal an effective amount of a compound of the invention,thereby enhancing the effect. In an exemplary embodiment, the compoundis according to a formula described in the section entitled “Inhibitinga phosphodiesterase”. In an exemplary embodiment, the compound is amember selected from C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12,C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26,C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40,C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, C52, C53, C54,C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65, C66, C67, C68,C69, C70, C71, C72, C73, C74, C75, C76, C77, C78, C79, C80, C81, C82,C83, C84, C85, C86, C87, C88, C89, C90, C91, C92, C93, C94, C95, C96,C97, C98, C99 and C100. In an exemplary embodiment, the compound is amember selected from D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12,D13, D14, D15, D16, D17, D18, D19, D20, D21, D22, D23, D24, D25, D26,D27, D28, D29, D30, D31, D32, D33, D34, D35, D36, D37, D38, D39, D40,D41, D42, D43, D44, D45, D46, D47, D48, D49, D50, D51, D52, D53, D54,D55, D56, D57, D58, D59, D60, D61, D62, D63, D64, D65, D66, D67, D68,D69, D70, D71, D72, D73, D74, D75, D76, D77, D78, D79, D80, D81, D82,D83, D84, D85, D86, D87, D88, D89, D90, D91, D92, D93, D94, D95, D96,D97, D98, D99, D100, D101, D102, D103, D104, D105, D106, D107, D108,D109, D110, D111, D112, D113, D114, D115, D116, D117, D118, D119, D120,D121, D122, D123, D124, D125, D126, D127, D128, D129, D130, D131, D132,D133, D134, D135, D136, D137, D138, D139, D140, D141, D142, D143, D144,D145, D146, D147, D148, D149, D150, D151, D152, D153, D154, D155, D156,D157, D158, D159, D160, D161, D162, D163, D164, D165, D166, D167, D168,D169, D170, D171, D172, D173, D174, D175, D176, D177, D178, D179, D180,D181, D182, D183, D184, D185, D186, D187, D188, D189, D190, D191, D192,D193, D194, D195, D196, D197, D198, D199, D200, D201, D202, D203, D204,D205, D206, D207, D208, D209, D210, D211, D212, D213, D214, D215, D216,D217, D218, D219, D220, D221, D222, D223, D224, D225, D226, D227, D228and D229. In an exemplary embodiment, the compound is C17 or apharmaceutically acceptable salt thereof. In an exemplary embodiment,the compound is C27 or a pharmaceutically acceptable salt thereof. In anexemplary embodiment, the compound is a member selected from D46, D86,D99, D100, D107, D108, D114, D122, D125, D126, D127, D128, D131, D140and D141, and salts thereof. In an exemplary embodiment, the compound isa member selected from D95, D96, D97, D102, D110, D111, D113, D115,D121, D129, D130, D132, and salts thereof. In an exemplary embodiment,the compound is a member selected from D47, D109, D116, D118, D119,D120, D123, and salts thereof. In an exemplary embodiment, the compoundis a member selected from D98, D101, D106, and salts thereof. In anexemplary embodiment, the compound is a member selected from D11, D12,D37, D38, D39, D40, D41, D42, D43, D124, D142, D143, D146, and saltsthereof. In an exemplary embodiment, the compound is a member selectedfrom D14, D15, D16, D17, D28, D29, D30, D31, D133, D134, D135, D144,D145, D147, and salts thereof.

In an exemplary embodiment, the condition is a disease. In an exemplaryembodiment, the condition is an inflammatory-related condition. In anexemplary embodiment, the condition involves the increase of productionof a cytokine and/or a chemokine. In an exemplary embodiment, thecondition involves the decrease of production of a cytokine and/or achemokine. In an exemplary embodiment, the condition involves theincrease of release of a cytokine and/or a chemokine. In an exemplaryembodiment, the condition involves the decrease of release of a cytokineand/or a chemokine. In an exemplary embodiment, the condition involvesthe inhibition of a phosphodiesterase. In an exemplary embodiment, thecompound is in an amount sufficient to treat the inflammatory-relateddisease by inhibiting pro-inflammatory cytokine expression or bystimulating anti-inflammatory cytokine expression, but the amount isless than sufficient to substantially inhibit cyclin dependent kinases.In an exemplary embodiment, the condition is mediated by a cytokine. Inan exemplary embodiment, the condition is mediated by a chemokine. In anexemplary embodiment, the condition is mediated by a neutrophil. In anexemplary embodiment, the condition is mediated by a phosphodiesterase.In an exemplary embodiment, the condition is mediated by aphosphodiesterase-4. In an exemplary embodiment, the condition ismediated by a phosphodiesterase-7.

In an exemplary embodiment, the condition is a member selected fromperiodontitis, keratoconjunctivitis sicca, rheumatoid arthritis,osteoarthritis, Crohn's disease, ulcerative colitis, psoriaticarthritis, traumatic arthritis, rubella arthritis, inflammatory boweldisease, multiple sclerosis, psoriasis, graft versus host disease,systemic lupus erythematosus, cutaneous lupus erythematosus, toxic shocksyndrome, irritable bowel syndrome, muscle degeneration, allograftrejections, pancreatitis, insulinitis, glomerulonephritis, diabeticnephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acutesynovitis, Reiter's syndrome, gouty arthritis, Behcet's disease,spondylitis, endometriosis, non-articular inflammatory conditions, suchas intervertebral disk syndrome conditions, bursitis, tendonitis,tenosynovitis or fibromyalgic syndrome; and acute or chronic pain,including but not limited to neurological pain, neuropathies,polyneuropathies, diabetes-related polyneuropathies, trauma, migraine,tension and cluster headache, Horton's disease, varicose ulcers,neuralgias, musculo-skeletal pain, osteo-traumatic pain, fractures,algodystrophy, spondylarthritis, fibromyalgia, phantom limb pain, backpain, vertebral pain, post-surgery pain, herniated intervertebraldisc-induced sciatica, cancer-related pain, vascular pain, visceralpain, childbirth, or HIV-related pain. Other cytokine mediated diseasesare allergy, a metabolic disease, a chemotherapy/radiation relatedcomplication; diabetes type I; diabetes type II; a liver disease; agastrointestinal disorder; an ophthamological disease; allergicconjunctivitis; diabetic retinopathy; Sjogren's syndrome; uvetitis; apulmonary disorder, a renal disease; dermatitis; HIV-related cachexia;cerebral malaria; ankylosing spondolytis; leprosy; anemia; fibromyalgia,kidney failure, stroke, chronic heart failure, endotoxemia, reperfusioninjury, ischemia reperfusion, myocardial ischemia, restenosis,thrombosis, angiogenesis, Coronary Heart Disease, Coronary ArteryDisease, acute coronary syndrome, Takayasu arteritis, cardiac failuresuch as heart failure, aortic valve stenosis, cardiomyopathy,myocarditis, vasculitis, vascular restenosis, valvular disease orcoronary artery bypass; hypercholesteremia, diseases or conditionsrelated to blood coagulation or fibrinolysis, such as for example, acutevenous thrombosis, pulmonary embolism, thrombosis during pregnancy,hemorrhagic skin necrosis, acute or chronic disseminated intravascularcoagulation (DIC), clot formation from surgery, long bed rest or longperiods of immobilization, venous thrombosis, fulminant meningococcemia,acute thrombotic strokes, acute coronary occlusion, acute peripheralarterial occlusion, massive pulmonary embolism, axillary veinthrombosis, massive iliofemoral vein thrombosis, occluded arterial orvenous cannulae, cardiomyopathy, venoocclusive disease of the liver,hypotension, decreased cardiac output, decreased vascular resistance,pulmonary hypertension, diminished lung compliance, leukopenia orthrombocytopenia; or atherosclerosis.

In an exemplary embodiment, the condition is a member selected fromallergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinalischemia, diabetic retinopathy, laser induced optic damage, or surgeryor trauma-induced proliferative vitreoretinopathy.

In an exemplary embodiment, the condition is a member selected fromallergic rhinitis, asthma, adult respiratory distress syndrome, chronicpulmonary inflammation, chronic obstructive pulmonary disease,emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infectionand respiratory tract inflammation.

In an exemplary embodiment, the condition is a member selected frompsoriasis, eczema, atopic dermatitis, contact dermatitis, inflammatoryalopecia or acne.

In an exemplary embodiment, the condition is a member selected fromGuillain-Barre syndrome, Parkinson's disease, Huntington's disease,Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosisand other demyelinating diseases, viral and bacterial meningitis, CNStrauma, spinal cord injury, seizures, convulsions, olivopontocerebellaratrophy, AIDS dementia complex, MERRF and MELAS syndromes, Leber'sdisease, Wemicke's encephalophathy, Rett syndrome, homocysteinuria,hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia,hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combinedsystems disease, lead encephalopathy, Tourett's syndrome, hepaticencephalopathy, drug addiction, drug tolerance, drug dependency,depression, attention deficit disorder (ADD), anxiety and schizophrenia,aneurism, or epilepsy.

In an exemplary embodiment, the condition is a member selected from boneresorption diseases, osteopetrosis, osteoporosis, or osteoarthritis.

In an exemplary embodiment, the condition is a member selected fromdiabetes, systemic cachexia, cachexia secondary to infection ormalignancy, cachexia secondary to acquired immune deficiency syndrome(AIDS), obesity, anorexia or bulimia nervosa. In an exemplaryembodiment, the condition is a member selected from sepsis, HIV, HCV,malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer,including but not limited to breast cancer, colon cancer, lung cancer,prostate cancer, multiple myeloma, acute myelogenous leukemia,myelodysplastic syndrome, non-Hodgkins lymphoma, or follicular lymphoma,Castleman's disease, or drug resistance.

In an exemplary embodiment, the condition is a member selected from isbronchial asthma, rhinitis, influenza, stroke, myocardial infarction,thermal injury, adult respiratory distress syndrome (ARDS), multipleorgan injury secondary to trauma, acute glomerulonephritis, dermatoseswith acute inflammatory components, acute purulent meningitis,hemodialysis, leukopheresis, granulocyte transfusion associatedsyndromes, or necrotizing enterocolitis.

In an exemplary embodiment, the condition is a member selected frominflammatory bowel disease (IBD), psoriasis, rheumatoid arthritis (RA),multiple sclerosis (MS), neurodegenerative disorder, cardiovasculardisease (CVD) and atherosclerosis, and metabolic disease (the metabolicsyndrome and diabetes) as well as infection-related inflammation. In anexemplary embodiment, the condition is a neurodegenerative disorderwhich is a member selected from Alzheimer's disease and Parkinsondisease. In an exemplary embodiment, the condition is inflammatory boweldisease which is selected from the group consisting of: Crohn's diseaseor ulcerative colitis. In an exemplary embodiment, the condition is agastrointestinal complication. In an exemplary embodiment, the conditionis diarrhea. In an exemplary embodiment, the condition is a memberselected from celiac disease and non-specific colitis. In an exemplaryembodiment, the condition is a liver disease. In an exemplaryembodiment, the condition is a member selected from an autoimmunehepatitis, hepatitis C, primary biliary cirrhosis, primary sclerosingcholangitis, or fulminant liver failure. In an exemplary embodiment, thecondition is a bone disease. In an exemplary embodiment, the conditionis osteoporosis. In an exemplary embodiment, the condition is apulmonary disorder. In an exemplary embodiment, the condition is amember selected from: allergic rhinitis, asthma, chronic obstructivepulmonary disease, chronic granulomatous inflammation, cystic fibrosis,and sarcoidosis. In an exemplary embodiment, condition is cardiovasculardisease. In an exemplary embodiment, the cardiovascular disease is amember selected from atherosclerotic cardiac disease, congestive heartfailure and restenosis. In an exemplary embodiment, the condition is arenal disease. In an exemplary embodiment, the condition is a memberselected from glomerulonephritis and vasculitis. In an exemplaryembodiment, the condition is a member selected from post-radiotherapyrelated disease or atherosclerosis. In yet another embodiment thecondition is atopic dermatitis. In yet another embodiment the conditionis actinic keratosis.

In an exemplary embodiment, the condition is a member selected frompsoriasis, inflammatory arthritis, rheumatoid arthritis, asthma, chronicbronchitis, inflammatory bowel disease (IBD), chronic obstructivepulmonary disease (COPD), atopic dermatitis, urticaria, allergicrhinitis, allergic conjunctivitis, vernal conjunctivitis, colitis,esoniophilic granuloma, septic shock, reperfusion injury of themyocardium, reperfusion injury of the brain, chronic glomerulonephritis,endotoxic shock, adult respiratory distress syndrome, cystic fibrosis,arterial restenosis, artherosclerosis, keratosis, rheumatoidspondylitis, osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis,chronic obstructive airways disease, toxic contact eczema, allergiccontact eczema, atopic eczema, seborrheic eczema, lichen simplex,sunburn, pruritis in the anogenital area, alopecia greata, hypertrophicscars, discoid lupus erythematosus, systemic lupus erythematosus,follicular pyodermias, wide-area pyodermias, endogenous acne, exogenousacne, acne rosacea, Behcet's disease, anaphylactoid purpura nephritis,leukemia, multiple sclerosis, gastrointestinal disease and autoimmunedisease. In an exemplary embodiment, the colitis is a member selectedfrom ulcerative colitis, Crohn's colitis, diversion colitis, ischemiccolitis, infectious colitis, fulminant colitis, chemical colitis,microscopic colitis, lymphocytic colitis, and atypical colitis. In anexemplary embodiment, the colitis is a member selected from ulcerativecolitis and Crohn's colitis. In an exemplary embodiment, the conditionis sunburn. In an exemplary embodiment, the condition is inflammationcaused by sunburn.

In an exemplary embodiment, the condition is psoriasis. In an exemplaryembodiment, psoriasis is a member selected from plaque psoriasis,flexural psoriasis (inverse psoriasis), guttate psoriasis, pustularpsoriasis, nail psoriasis, psoriatic arthritis and erythrodermicpsoriasis. In an exemplary embodiment, the psoriasis is a memberselected from plaque psoriasis and nail psoriasis. In an exemplaryembodiment, the condition is psoriasis and the compound is C17. In anexemplary embodiment, the condition is psoriasis and the compound isC27. In an exemplary embodiment, the condition is plaque psoriasis ornail psoriasis and the compound is C17. In an exemplary embodiment, thecondition is plaque psoriasis or nail psoriasis and the compound is C27.

In an exemplary embodiment, the disorder is a member selected fromcognition impairment or decline and memory impairment. In an exemplaryembodiment, the memory impairment is due to dementia. In an exemplaryembodiment, the patient is suffering from memory impairment due toAlzheimer's disease, schizophrenia, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeld-Jakob disease, depression, aging,head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarctdementia, an acute neuronal disease, age-related cognitive decline, HIVor a cardiovascular disease.

In an exemplary embodiment, the PDE4 inhibition is enhancing an effect,wherein the enhanced effect is cognition or memory.

In an exemplary embodiment, the invention provides a method forstimulating ovarian follicular growth in a female, comprisingadministering to a female a medicament comprising a compound of theinvention, whereby ovarian follicular growth is stimulated in thefemale. In an exemplary embodiment, the compound of the invention is acompound described herein or a pharmaceutically acceptable salt thereof.In an exemplary embodiment, the female is undergoing ovulationinduction. In an exemplary embodiment, the female is undergoingcontrolled ovarian hyperstimulation. In an exemplary embodiment, themedicament is administered simultaneously, separately or sequentiallywith follicle stimulating hormone (FSH), or an agent having FSHactivity, or an agent that stimulates endogenous FSH release.

The invention also provides a method of treating an inflammatory-relateddisease associated with cytokine expression levels, which comprisesadministering to an animal in need of such treatment the compound of theinvention. In an exemplary embodiment, the compound is according to aformula described herein. In an exemplary embodiment, the compound ofthe invention is a compound described herein or a pharmaceuticallyacceptable salt thereof.

In an exemplary embodiment, the invention provides a method of treatingor preventing an inflammatory-related disease in an animal, the methodcomprising administering to the animal a therapeutically effectiveamount of a compound of the invention, wherein the compound is in anamount sufficient to treat the inflammatory-related disease byinhibiting pro-inflammatory cytokine expression or by stimulatinganti-inflammatory cytokine expression, but the amount is less thansufficient to substantially inhibit cyclin dependent kinases. In anexemplary embodiment, the compound of the invention is a compounddescribed herein or a pharmaceutically acceptable salt thereof.

In an exemplary embodiment, the invention provides a method forinhibiting the production of an inflammatory cytokine by cells capableof producing the inflammatory cytokine, the method comprises contactinga cell with a therapeutic amount of compound of the invention, whereinproduction of the inflammatory cytokine by the cells is inhibited. In anexemplary embodiment, the therapeutic amount is sufficient to inhibitthe production of the inflammatory cytokine protein between about 50%and about 99%.

In an exemplary embodiment, the invention provides a method forinhibiting an inflammatory response in an animal, the method comprising:contacting the animal with a therapeutic amount of a compound of theinvention, wherein the inflammatory response is inhibited.

In an exemplary embodiment, for any of the methods described herein, theanimal is a member selected from human, cattle, deer, reindeer, goat,honey bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil,rabbit, cat, camel, yak, elephant, ostrich, otter, chicken, duck, goose,guinea fowl, pigeon, swan, and turkey. In another exemplary embodiment,for any of the methods described herein, the animal is a member selectedfrom a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guineapig, gerbil, rabbit, cat, chicken and turkey. In another exemplaryembodiment, for any of the methods described herein, the animal is ahuman.

In an exemplary embodiment, for any of the methods described herein, acompound of the invention and/or a pharmaceutical formulation describedherein can be used.

In another exemplary embodiment, in any of the methods oftreating/preventing a condition or enhancing an effect described herein,the animal being administered the compound of the invention is nototherwise in need of treatment with the compound of the invention. In anexemplary embodiment, the compound is a member selected from C1, C2, C3,C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18,C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32,C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46,C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60,C61, C62, C63, C64, C65, C66, C67, C68, C69, C70, C71, C72, C73, C74,C75, C76, C77, C78, C79, C80, C81, C82, C83, C84, C85, C86, C87, C88,C89, C90, C91, C92, C93, C94, C95, C96, C97, C98, C99 and C100. In anexemplary embodiment, the compound is C17. In an exemplary embodiment,the compound is C27. In an exemplary embodiment, the compound is D1. Inan exemplary embodiment, the compound is D82. In an exemplaryembodiment, the compound is D226. In an exemplary embodiment, thecompound is D227.

In another exemplary embodiment, the method involves treating psoriasisby administering a compound of the invention to an animal not otherwisein need of treatment with the compounds of the invention.

In another exemplary embodiment, the method involves treating atopicdermatitis by administering a compound of the invention to an animal nototherwise in need of treatment with the compounds of the invention.

V. Pharmaceutical Formulations

In another aspect, the invention provides a pharmaceutical formulationcomprising: (a) a compound of the invention and (b) a pharmaceuticallyacceptable excipient. In an exemplary embodiment, the compound of theinvention is a compound described herein or a pharmaceuticallyacceptable salt thereof. In an exemplary embodiment, the compound of theinvention is a compound described herein or a pharmaceuticallyacceptable salt thereof. In an exemplary embodiment, the compound isaccording to a formula described herein. In an exemplary embodiment, thecompound is a member selected from C1, C2, C3, C4, C5, C6, C7, C8, C9,C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23,C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37,C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51,C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, C63, C64, C65,C66, C67, C68, C69, C70, C71, C72, C73, C74, C75, C76, C77, C78, C79,C80, C81, C82, C83, C84, C85, C86, C87, C88, C89, C90, C91, C92, C93,C94, C95, C96, C97, C98, C99 and C100. In an exemplary embodiment, thecompound is a member selected from D1, D2, D3, D4, D5, D6, D7, D8, D9,D10, D11, D12, D13, D14, D15, D16, D17, D18, D19, D20, D21, D22, D23,D24, D25, D26, D27, D28, D29, D30, D31, D32, D33, D34, D35, D36, D37,D38, D39, D40, D41, D42, D43, D44, D45, D46, D47, D48, D49, D50, D51,D52, D53, D54, D55, D56, D57, D58, D59, D60, D61, D62, D63, D64, D65,D66, D67, D68, D69, D70, D71, D72, D73, D74, D75, D76, D77, D78, D79,D80, D81, D82, D83, D84, D85, D86, D87, D88, D89, D90, D91, D92, D93,D94, D95, D96, D97, D98, D99, D100, D101, D102, D103, D104, D105, D106,D107, D108, D109, D110, D111, D112, D113, D114, D115, D116, D117, D118,D119, D120, D121, D122, D123, D124, D125, D126, D127, D128, D129, D130,D131, D132, D133, D134, D135, D136, D137, D138, D139, D140, D141, D142,D143, D144, D145, D146, D147, D148, D149, D150, D151, D152, D153, D154,D155, D156, D157, D158, D159, D160, D161, D162, D163, D164, D165, D166,D167, D168, D169, D170, D171, D172, D173, D174, D175, D176, D177, D178,D179, D180, D181, D182, D183, D184, D185, D186, D187, D188, D189, D190,D191, D192, D193, D194, D195, D196, D197, D198, D199, D200, D201, D202,D203, D204, D205, D206, D207, D208, D209, D210, D211, D212, D213, D214,D215, D216, D217, D218, D219, D220, D221, D222, D223, D224, D225, D226,D227, D228 and D229. In an exemplary embodiment, the compound is C17. Inan exemplary embodiment, the compound is C27. In an exemplaryembodiment, the formulation is a unit dosage form. In an exemplaryembodiment, the formulation is a member selected from an oral unitdosage form and a topical unit dosage form. In an exemplary embodiment,the topical unit dosage form is a member selected from a lotion, anointment and a cream. In an exemplary embodiment, the formulation is fortopical use.

In an exemplary embodiment, the compound of the invention is present inthe pharmaceutical formulation in an amount of between about 0.0001% toabout 60% (w/w). In an exemplary embodiment, the amount is between about0.05% to about 0.2% (w/w). In an exemplary embodiment, the amount isbetween about 0.075% to about 0.15% (w/w). In an exemplary embodiment,the amount is between about 0.01% to about 10% (w/w). In an exemplaryembodiment, the amount is between about 0.1% to about 10% (w/w). In anexemplary embodiment, the amount is between about 0.25% to about 6%(w/w). In an exemplary embodiment, the amount is between about 0.5% toabout 5% (w/w). In an exemplary embodiment, the amount is between about0.1% and about 1.0% (w/w). In an exemplary embodiment, the amount isbetween about 0.25% and about 0.75% (w/w). In an exemplary embodiment,the amount is between about 0.4% and about 0.6% (w/w). In an exemplaryembodiment, the amount is between about 1.0% and about 2.0% (w/w). In anexemplary embodiment, the amount is between about 1.3% and about 1.7%(w/w). In an exemplary embodiment, the amount is between about 2.0% andabout 3.0% (w/w). In an exemplary embodiment, the amount is betweenabout 3.0% and about 4.0% (w/w). In an exemplary embodiment, the amountis between about 4.0% and about 5.0% (w/w). In an exemplary embodiment,the amount is between about 4.5% and about 5.5% (w/w). In an exemplaryembodiment, the amount is between about 10% to about 20% (w/w). In anexemplary embodiment, the amount is between about 13% to about 17%(w/w). In an exemplary embodiment, the amount is between about 14% toabout 16% (w/w). In an exemplary embodiment, the amount is a memberselected from about 0.1%, 0.3, 0.5%, 1.0%, 1.5%, 2.0%, 5.0%, 10% and 15%(w/w).

The pharmaceutical formulations of the invention can take a variety offorms adapted to the chosen route of administration. Those skilled inthe art will recognize various synthetic methodologies that may beemployed to prepare non-toxic pharmaceutical formulations incorporatingthe compounds described herein. Those skilled in the art will recognizea wide variety of non-toxic pharmaceutically acceptable solvents thatmay be used to prepare solvates of the compounds of the invention, suchas water, ethanol, propylene glycol, mineral oil, vegetable oil anddimethylsulfoxide (DMSO).

The pharmaceutical formulations of the invention may be administeredorally, topically, ocularly, parenterally, by inhalation or spray orrectally in dosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. It isfurther understood that the best method of administration may be acombination of methods. Oral administration in the form of a pill,capsule, elixir, syrup, lozenge, troche, or the like is particularlypreferred. The term parenteral as used herein includes subcutaneousinjections, intradermal, intravascular (e.g., intravenous),intramuscular, spinal, intrathecal injection or like injection orinfusion techniques.

The pharmaceutical formulations containing compounds of the inventionare preferably in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Pharmaceutical formulations intended for oral use may be preparedaccording to any method known in the art for the manufacture ofpharmaceutical formulations, and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tablets maycontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients that are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia; lubricating agents, for example magnesiumstearate, stearic acid or talc; and extenders and bulking agents, suchas microcrystalline cellulose. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;and dispersing or wetting agents, which may be a naturally-occurringphosphatide, for example, lecithin, or condensation products of analkylene oxide with fatty acids, for example polyoxyethylene stearate,or condensation products of ethylene oxide with long chain aliphaticalcohols, for example heptadecaethyleneoxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol such as polyoxyethylene sorbitol monooleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one ormore coloring agents, one or more flavoring agents, and one or moresweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Other dispersing agents include hydrophilic polymers, electrolytes,Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known asPlasdone®), and the carbohydrate-based dispersing agents such as, forexample, hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g.,HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose andhydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMCK15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose,hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate stearate, noncrystalline cellulose,magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA),polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone®, e.g., S-630),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol), poloxamers (e.g., PluronicsF68®, F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); and poloxamines (e.g., Tetronic 9080, also known asPoloxamine 9080, which is a tetrafunctional block copolymer derived fromsequential addition of propylene oxide and ethylene oxide toethylenediamine (BASF Corporation, Parsippany, N.J.)). Additionalexcipients, for example sweetening, flavoring and coloring agents, mayalso be present.

Pharmaceutical formulations of the invention may also be in the form ofoil-in-water emulsions and water-in-oil emulsions. The oily phase may bea vegetable oil, for example olive oil or arachis oil, or a mineral oil,for example liquid paraffin or mixtures of these. Suitable emulsifyingagents may be naturally-occurring gums, for example gum acacia or gumtragacanth; naturally-occurring phosphatides, for example soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol; anhydrides, for example sorbitan monooleate; and condensationproducts of the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents. The pharmaceutical formulations may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents, which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The pharmaceutical formulations may also be administered in the form ofsuppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Alternatively, the pharmaceutical formulations can be administeredparenterally in a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

In some embodiments, the pharmaceutical formulations may be administeredocularly. In some embodiments, the ophthalmic formulation contains aliquid vehicle. The compound, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle. Suchophthalmic formulations can then be administered to the eye in the formof a droplet. Suitable vehicles, and optional tear substitutecomponents, are known in the art.

For administration to non-human animals, the composition containing thetherapeutic compound may be added to the animal's feed or drinkingwater. Also, it will be convenient to formulate animal feed and drinkingwater products so that the animal takes in an appropriate quantity ofthe compound in its diet. It will further be convenient to present thecompound in a composition as a premix for addition to the feed ordrinking water. The composition can also added as a food or drinksupplement for humans.

Dosage levels of the order of from about 5 mg to about 250 mg perkilogram of body weight per day and more preferably from about 25 mg toabout 150 mg per kilogram of body weight per day, are useful in thetreatment of the above-indicated conditions. The amount of activeingredient that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the condition being treatedand the particular mode of administration. Dosage unit forms willgenerally contain between from about 1 mg to about 500 mg of an activeingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily or less is preferred. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration and rate ofexcretion, drug combination and the severity of the particular diseaseundergoing therapy.

Preferred compounds of the invention will have desirable pharmacologicalproperties that include, but are not limited to, oral bioavailability,low toxicity, low serum protein binding and desirable in vitro and invivo half-lives. Penetration of the blood brain barrier for compoundsused to treat CNS disorders is necessary, while low brain levels ofcompounds used to treat peripheral disorders are often preferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocytes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of laboratory animalsthat receive the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcova, et al. (Journal ofChromatography B (1996) volume 677, pages 1-27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lives of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

The amount of the composition required for use in treatment will varynot only with the particular compound selected but also with the routeof administration, the nature of the condition being treated and the ageand condition of the patient and will ultimately be at the discretion ofthe attendant physician or clinician.

In an exemplary embodiment, the pharmaceutical composition describedherein includes an additional active ingredient. In another exemplaryembodiment, the additional active ingredient is an immunosuppressiveagent. In still another exemplary embodiment, the additional activeingredient is a member selected from corticosteroids, aminosalicylates,azathioprine (6-mercaptopurine), methotrexate and ciclosporine,etanercept, infliximab, adalimumab, alefacept, efalizumab and anakinra.

In an exemplary embodiment, the additional active ingredient is a memberselected from cilostazol, rolipram, roflumilast, piclamilast, CDP-840and ariflo.

In still another exemplary embodiment, the additional active ingredientis a member selected from betamethasone, tacrolimus and pimecrolimus. Instill another exemplary embodiment, the additional active ingredient isa member selected from an activated vitamin D analog and an arotinoid(an aromatic retinoic acid analog). In still another exemplaryembodiment, the additional active ingredient is a member selected fromcarcipotriol, such as Tazorac (tazarotene).

V. a) Topical Formulations

In a preferred embodiment, the methods of the invention can be employedthrough the topical application of the compounds described herein.Topical administration includes for example, transmucosal, transdermal,ungual and transungual routes of administration.

The compositions of the present invention comprises fluid or semi-solidvehicles that may include but are not limited to polymers, thickeners,buffers, neutralizers, chelating agents, preservatives, surfactants oremulsifiers, antioxidants, waxes or oils, emollients, sunscreens, and asolvent or mixed solvent system. The solvent or mixed solvent system isimportant to the formation because it is primarily responsible fordissolving the drug. The best solvent or mixed solvent systems are alsocapable of maintaining clinically relevant levels of the drug insolution despite the addition of a poor solvent to the formulation. Thetopical compositions useful in the subject invention can be made into awide variety of product types. These include, but are not limited to,lotions, creams, gels, sticks, sprays, ointments, pastes, foams,mousses, masks, eye ointments, eye or ear drops, impregnated dressings,wipes, cleansers including soaps, body washes and shampoos, and make-upproducts, such as bases, blushes, lipsticks, and eye shadows, amongothers. These product types can comprise several types of carriersystems including, but not limited to particles, nanoparticles, andliposomes. If desired, disintegrating agents can be added, such as thecross-linked polyvinyl pyrrolidone, agar or alginic acid or a saltthereof such as sodium alginate. Techniques for formulation andadministration can be found in Remington: The Science and Practice ofPharmacy, supra. The formulation can be selected to maximize delivery toa desired target site in the body. The formulations can also includevarious conventional colorants, fragrances, thickeners, preservatives,humectants, emollients, demulcents, solubilizing excipients,dispersants, penetration enhancers, plasticizing agents, preservatives,stabilizers, demulsifiers, wetting agents, sunscreens, emulsifiers,moisturizers, astringents, deodorants, and the like, which can be addedto provide additional benefits such as, for example, improving the feeland/or appearance of the topical preparation.

Lotions, which are preparations that are to be applied to the skin,nail, hair, claw or hoof surface without friction, are typically liquidor semi-liquid preparations in which finely divided solid, waxy, orliquid are dispersed. Lotions will typically contain suspending agentsto produce better dispersions as well as compounds useful for localizingand holding the active agent in contact with the skin, nail, hair, clawor hoof, e.g., methylcellulose, sodium carboxymethyl-cellulose, or thelike.

Creams containing the active agent for delivery according to the presentinvention are viscous liquid or semisolid emulsions, either oil-in-wateror water-in-oil. Cream bases are water-washable, and contain an oilphase, an emulsifier and an aqueous phase. The oil phase is generallycomprised of petrolatum or a fatty alcohol, such as cetyl- or stearylalcohol; the aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation, as explained in Remington: TheScience and Practice of Pharmacy, supra, is generally a nonionic,anionic, cationic or amphoteric surfactant.

A lotion or cream may include a relatively large aqueous phase and arelatively small oil phase. Furthermore, the lotions and creams of theinvention may include the active compound “all-in-solution” in the oilphase so that substantially none of the active compound crystallizes outat room temperature. In one embodiment, the lotion or cream may comprisea biphasic system, that is, a system wherein a portion (from about 30 toabout 75% by weight) of the active compound is in solution in the oilphase and the remainder is in suspension in the aqueous phase.

Gel formulations can also be used in connection with the presentinvention. As will be appreciated by those working in the field oftopical drug formulation, gels are semisolid. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe carrier liquid, which is typically aqueous, but also may be asolvent or solvent blend. In various embodiments, conventional gellingagents can be used. In an exemplary embodiment, cellulose or itsderivatives are used. In an exemplary embodiment, hydroxypropyl methylcellulose, such as Methocel E4M, is used. Other gelling agents includemethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate, ethyl cellulose, methyl hydroxy ethylcellulose, hydroxy ethyl cellulose, and cellulose gum. Cellulose basedgelling agents, particularly hydroxymethylcellulose and hydroxypropylmethyl cellulose, are also useful in some embodiments. In someembodiments, cross-linked acrylic polymers including Carbopol may beused.

In one embodiment, the formulation of the invention is viscous enough toform a firm gel. In one embodiment, the viscosity is in the range of25,000-300,000 cps (centipoise) or 75,000-200,000 cps, based onBrookfield (LV) analysis.

For ease of preparation, it may be convenient to prepare a first gelcomposition, named speed-gel herein, which can be used to add to othercomponents in the formulation of a final composition for topicaladministration. There are several possible formulations of thespeed-gel. For example, a speed-gel may be prepared by mixing lecithinorganogel (L.O.), as a 1:1 (m/m) mixture of lecithin and isopropylmyristate, with LID oil (a 1:1 [m/m] mixture of L.O. and docusatesodium), dissolving additional docusate sodium powder into this mixture,and then adding aqueous urea.

Ointments, which are semisolid preparations, are typically based onpetrolatum or other petroleum derivatives. As will be appreciated by theordinarily skilled artisan, the specific ointment base to be used is onethat provides for optimum delivery for the active agent chosen for agiven formulation, and, preferably, provides for other desiredcharacteristics as well, e.g., emolliency or the like. As with othercarriers or vehicles, an ointment base should be inert, stable,nonirritating and non-sensitizing. As explained in Remington: TheScience and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack PublishingCo., 1995), at pages 1399-1404, ointment bases may be grouped in fourclasses: oleaginous bases; emulsifiable bases; emulsion bases; andwater-soluble bases. Oleaginous ointment bases include, for example,vegetable oils, fats obtained from animals, and semisolid hydrocarbonsobtained from petroleum. Examples of oleaginous ointment bases includeWhite Ointment USP, Yellow Ointment NF, Oleic Acid USP, Olive Oil USP,Paraffin USP, Petrolatum NF, White Petrolatum USP, Spermaceti Wax USP,Synthetic Spermaceti NF, Starch Glycerite NF, White Wax USP, and YellowWax USP. Emulsifiable ointment bases, also known as absorbent ointmentbases, contain little or no water and include, for example,hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.Emulsion ointment bases are either water-in-oil (W/O) emulsions oroil-in-water (O/W) emulsions, and include, for example, cetyl alcohol,glyceryl monostearate, lanolin and stearic acid. Preferred water-solubleointment bases are prepared from polyethylene glycols of varyingmolecular weight; again, reference may be had to Remington: The Scienceand Practice of Pharmacy, supra, for further information.

Useful formulations of the invention also encompass sprays and aerosols.Sprays generally provide the active agent in an aqueous and/or alcoholicsolution which can be misted onto the skin, nail, hair, claw or hoof fordelivery. Such sprays include those formulated to provide forconcentration of the active agent solution at the site of administrationfollowing delivery, e.g., the spray solution can be primarily composedof alcohol or other like volatile liquid in which the drug or activeagent can be dissolved. Upon delivery to the skin, nail, hair, claw orhoof, the carrier evaporates, leaving concentrated active agent at thesite of administration. Examples of aerosol technology are disclosed inU.S. Pat. Nos. 6,682,716; 6,716,415; 6,716,417; 6,783,753; 7,029,658;and 7,033,575.

The topical pharmaceutical compositions may also comprise suitable solidor gel phase carriers. Examples of such carriers include but are notlimited to calcium carbonate, calcium phosphate, various sugars,starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols.

The topical pharmaceutical compositions may also comprise a suitableemulsifier which refers to an agent that enhances or facilitates mixingand suspending oil-in-water or water-in-oil. The emulsifying agent usedherein may consist of a single emulsifying agent or may be a nonionic,anionic, cationic or amphoteric surfactant or blend of two or more suchsurfactants; preferred for use herein are nonionic or anionicemulsifiers. Such surface-active agents are described in “McCutcheon'sDetergent and Emulsifiers,” North American Edition, 1980 Annualpublished by the McCutcheon Division, MC Publishing Company, 175 RockRoad, Glen Rock, N.J. 07452, USA.

Examples of useful ionic surfactants include sodium caproate, sodiumcaprylate, sodium caprate, sodium laurate, sodium myristate, sodiummyristolate, sodium palmitate, sodium palmitoleate, sodium oleate,sodium ricinoleate, sodium linoleate, sodium linolenate, sodiumstearate, sodium lauryl sulfate (dodecyl), sodium tetradecyl sulfate,sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodiumcholate, sodium taurocholate, sodium glycocholate, sodium deoxycholate,sodium taurodeoxycholate, sodium glycodeoxycholate, sodiumursodeoxycholate, sodium chenodeoxycholate, sodiumtaurochenodeoxycholate, sodium glyco cheno deoxycholate, sodiumcholylsarcosinate, sodium N-methyl taurocholate, egg yolk phosphatides,hydrogenated soy lecithin, dimyristoyl lecithin, lecithin, hydroxylatedlecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin,phosphatidylcholine, phosphatidyl ethanolamine, phosphatidic acid,phosphatidyl glycerol, phosphatidyl serine, diethanolamine,phospholipids, polyoxyethylene-10 oleyl ether phosphate, esterificationproducts of fatty alcohols or fatty alcohol ethoxylates, with phosphoricacid or anhydride, ether carboxylates (by oxidation of terminal OH groupof, fatty alcohol ethoxylates), succinylated monoglycerides, sodiumstearyl fumarate, stearoyl propylene glycol hydrogen succinate,mono/diacetylated tartaric acid esters of mono- and diglycerides, citricacid esters of mono-, diglycerides, glyceryl-lacto esters of fattyacids, acyl lactylates, lactylic esters of fatty acids, sodiumstearoyl-2-lactylate, sodium stearoyl lactylate, alginate salts,propylene glycol alginate, ethoxylated alkyl sulfates, alkyl benzenesulfones, .alpha.-olefin sulfonates, acyl isethionates, acyl taurates,alkyl glyceryl ether sulfonates, sodium octyl sulfosuccinate, sodiumundecylenamideo-MEA-sulfosuccinate, hexadecyl triammonium bromide, decyltrimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecylammonium chloride, alkyl benzyldimethylammonium salts, diisobutylphenoxyethoxydimethyl benzylammonium salts, alkylpyridinium salts,betaines (trialkylglycine), lauryl betaine(N-lauryl,N,N-dimethylglycine), and ethoxylated amines(polyoxyethylene-15 coconut amine). For simplicity, typical counterionsare provided above. It will be appreciated by one skilled in the art,however, that any bioacceptable counterion may be used. For example,although the fatty acids are shown as sodium salts, other cationcounterions can also be used, such as, for example, alkali metal cationsor ammonium. Formulations of the invention may include one or more ofthe ionic surfactants above.

Preferred for use herein are high molecular weight alcohols such ascetearyl alcohol, cetyl alcohol, stearyl alcohol, emulsifying wax,glyceryl monostearate, and oleyl alcohol. Other examples are ethyleneglycol distearate, sorbitan tristearate, propylene glycol monostearate,sorbitan monooleate, sorbitan monostearate (SPAN 60), diethylene glycolmonolaurate, sorbitan monopalmitate, sucrose dioleate, sucrose stearate(CRODESTA F-160), polyoxyethylene lauryl ether (BRIJ 30),polyoxyethylene (2) stearyl ether (BRIJ 72), polyoxyethylene (21)stearyl ether (BRIJ 721), polyoxyethylene monostearate (Myrj 45),polyoxyethylene (20) sorbitan monolaurate (TWEEN 20, polysorbate 20),polyoxyethylene (20) sorbitan monopalmitate (TWEEN 40, polysorbate 40),polyoxyethylene (20) sorbitan monostearate (TWEEN 60, polysorbate 60),polyoxyethylene (20) sorbitan monooleate (TWEEN 80, polysorbate 80),other non-ionic polyoxyalkylene derivatives of hexitol anhydride partiallong chain fatty acid esters, and sodium oleate. In an exemplaryembodiment, the emulsifier is octyldodecanol. In an exemplaryembodiment, xanthan gum or a xanthan gum blend is used. Cholesterol andcholesterol derivatives may also be employed in externally usedemulsions and promote w/o emulsions.

Especially suitable nonionic emulsifying agents are those withhydrophile-lipophile balances (HLB) of about 3 to 6 for w/o system and 8to 18 for o/w system as determined by the method described by Paul L.Lindner in “Emulsions and Emulsion”, edited by Kenneth Lissant,published by Dekker, New York, N.Y., 1974, pages 188-190. More preferredfor use herein are one or more nonionic surfactants that produce asystem having HLB of about 8 to about 18.

Examples of such nonionic emulsifiers include but are not limited to“BRIJ 72”, the trade name for a polyoxyethylene (2) stearyl ether havingan HLB of 4.9; “BRIJ 721”, the trade name for a polyoxyethylene (21)stearyl ether having an HLB of 15.5, “Brij 30”, the trade name forpolyoxyethylene lauryl ether having an HLB of 9.7; “Polawax”, the tradename for emulsifying wax having an HLB of 8.0; “Span 60”, the trade namefor sorbitan monostearate having an HLB of 4.7; “Crodesta F-160”, thetrade name for sucrose stearate” having an HLB of 14.5. All of thesematerials are available from Ruger Chemicals Inc.; Croda; ICI Americas,Inc.; Spectrum Chemicals; and BASF. When the topical formulations of thepresent invention contain at least one emulsifying agent, eachemulsifying agent is present in amount from about 0.5 to about 2.5 wt %,preferably 0.5 to 2.0%, more preferably 1.0% or 1.8%. Preferably theemulsifying agent comprises a mixture of steareth 21 (at about 1.8%) andsteareth 2 (at about 1.0%).

The topical pharmaceutical compositions may also comprise suitableemollients. Emollients are materials used for the prevention or reliefof dryness, as well as for the protection of the skin, nail, hair, clawor hoof. Useful emollients include, but are not limited to, hydrocarbonoils, waxes, silicone, cetyl alcohol, isopropyl myristate, stearylalcohol, oleyl alcohol, octyl hydroxystearate, glycerin, other fattyalcohols including short or medium chain fatty alcohols having a carbonlength of up to 18, medium or short chain fatty acid triglycerides,esters such as fatty acid esters, lecithins and related polar compoundssuch as phosphatidylcholine, phosphatidylethanolamine,phosphatidylserine, phosphatidylinositol, phosphatidic acid,lyso-phosphatidylcholine, lyso-phosphatidylethanolamine, andsphingomyelin and the like. Other suitable emollients includetriglyceride oils like vegetable oils such as wheat germ, maize,sunflower, karite, castor, sweet almond, macadamia, apricot, soybean,cottonseed, alfalfa, poppy, pumpkinseed, sesame, cucumber, rapeseed,avocado, hazelnut, grape seed, blackcurrant seed, evening primrose,millet, barley, quinoa, olive, rye, safflower, candlenut, soya, palm,passion flower, or musk rose oil; triglycerides of caprylic/capric acid,such as those sold under the tradenames MIGLYOL® (Condea Chemie,Germany) and CRODAMOL (Croda, Inc., Edison, N.J.); fatty alcohols suchas caprylic alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol,and stearyl alcohol; and fatty esters such as oleyl acetate, isotridecylbenzoate, diisooctyl sebacate, isopropyl myristate, cetyl octanoate,isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate,decyl oleate, hexyldecyl dimethyloctanoate, cetyl lactate, myristyllactate, lanoline acetate, isocetyl stearate, isocetyl isostearate,cholesteryl 12-hydroxystearate, dipentaerythritol fatty acid ester, andisostearyl malate. A wide variety of suitable emollients are known andcan be used herein. See e.g., Sagarin, Cosmetics, Science andTechnology, 2nd Edition, Vol. 1, pp. 32-43 (1972), and U.S. Pat. No.4,919,934, to Deckner et al., issued Apr. 24, 1990, both of which areincorporated herein by reference in their entirety. These materials areavailable from Ruger Chemical Co, (Irvington, N.J.).

When the topical formulations of the present invention contain at leastone emollient, each emollient is present in an amount from about 0.1 to15%, preferably 0.1 to about 3.0, more preferably 0.5, 1.0, or 2.5 wt %.Preferably the emollient is a mixture of cetyl alcohol, isopropylmyristate and stearyl alcohol in a 1/5/2 ratio. The emollient may alsobe a mixture of cetyl alcohol and stearyl alcohol in a 1/2 ratio.

The topical pharmaceutical compositions may also comprise suitableantioxidants, substances known to inhibit oxidation. Antioxidantssuitable for use in accordance with the present invention include, butare not limited to, butylated hydroxytoluene, ascorbic acid, sodiumascorbate, calcium ascorbate, ascorbic palmitate, butylatedhydroxyanisole, 2,4,5-trihydroxybutyrophenone,4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum guaiac,propyl gallate, thiodipropionic acid, dilauryl thiodipropionate,tert-butylhydroquinone and tocopherols such as vitamin E, and the like,including pharmaceutically acceptable salts and esters of thesecompounds. Preferably, the antioxidant is butylated hydroxytoluene,butylated hydroxyanisole, propyl gallate, ascorbic acid,pharmaceutically acceptable salts or esters thereof, or mixturesthereof. Most preferably, the antioxidant is butylated hydroxytoluene.These materials are available from Ruger Chemical Co, (Irvington, N.J.).Antioxidants that may be incorporated into the formulations of theinvention include natural antioxidants prepared from plant extracts,such as extracts from aloe vera; avocado; chamomile; echinacea; ginkobiloba; ginseng; green tea; heather; jojoba; lavender; lemon grass;licorice; mallow; oats; peppermint; St. John's wort; willow;wintergreen; wheat wild yam extract; marine extracts; and mixturesthereof.

When the topical formulations of the present invention contain at leastone antioxidant, the total amount of antioxidant present is from about0.001 to 0.5 wt %, preferably 0.05 to about 0.5 wt %, more preferably0.1%.

The topical pharmaceutical compositions may also comprise suitablepreservatives. Preservatives are compounds added to a pharmaceuticalformulation to act as an anti-microbial agent. Among preservatives knownin the art as being effective and acceptable in parenteral formulationsare benzalkonium chloride, benzethonium, chlorohexidine, phenol,m-cresol, benzyl alcohol, methylparaben, propylparaben and otherparabens, chlorobutanol, o-cresol, p-cresol, chlorocresol,phenylmercuric nitrate, thimerosal, benzoic acid, and various mixturesthereof. See, e.g., Wallhausser, K.-H., Develop. Biol. Standard, 24:9-28(1974) (S. Krager, Basel). Preferably, the preservative is selected frommethylparaben, propylparaben and mixtures thereof. These materials areavailable from Inolex Chemical Co (Philadelphia, Pa.) or SpectrumChemicals.

When the topical formulations of the present invention contain at leastone preservative, the total amount of preservative present is from about0.01 to about 0.5 wt %, preferably from about 0.1 to 0.5%, morepreferably from about 0.03 to about 0.15. Preferably the preservative isa mixture of methylparaben and proplybarben in a 5/1 ratio. When alcoholis used as a preservative, the amount is usually 15 to 20%.

The topical pharmaceutical compositions may also comprise suitablechelating agents to form complexes with metal cations that do not crossa lipid bilayer. Examples of suitable chelating agents include ethylenediamine tetraacetic acid (EDTA), ethylene glycol-bis(beta-aminoethylether)-N,N,N′,N′-tetraacetic acid (EGTA) and8-Amino-2-[(2-amino-5-methylphenoxy)methyl]-6-methoxyquinoline-N,N,N′,N′-tetraaceticacid, tetrapotassium salt (QUIN-2). Preferably the chelating agents areEDTA and citric acid. A chelating agent may comprise salts of the above,such as edetate disodium, for example. These materials are availablefrom Spectrum Chemicals.

When the topical formulations of the present invention contain at leastone chelating agent, the total amount of chelating agent present is fromabout 0.005% to 2.0% by weight, preferably from about 0.05% to about 0.5wt %, more preferably about 0.1% by weight.

The topical pharmaceutical compositions may also comprise suitableneutralizing agents used to adjust the pH of the formulation to within apharmaceutically acceptable range. Examples of neutralizing agentsinclude but are not limited to trolamine, tromethamine, sodiumhydroxide, hydrochloric acid, sodium carbonate, citric acid, acetic acidand corresponding acids or bases thereof. Such materials are availablefrom are available from Spectrum Chemicals (Gardena, Calif.).

When the topical formulations of the present invention contain at leastone neutralizing agent, the total amount of neutralizing agent presentis from about 0.1 wt to about 10 wt %, preferably 0.1 wt % to about 5.0wt %, and more preferably about 1.0 wt %. The neutralizing agent isgenerally added in whatever amount is required to bring the formulationto the desired pH. In one embodiment, the pH is about 6.0 to about 8.0.In one embodiment, the pH is about 3.0 to about 4.0.

The topical pharmaceutical compositions may also comprise suitablethickening or viscosity increasing agents. These components arediffusible compounds capable of increasing the viscosity of apolymer-containing solution through the interaction of the agent withthe polymer. For example, CARBOPOL ULTREZ 10, polymethyl methacrylate(PMMA), and fumed silica may be used as a viscosity-increasing agent.These materials are available from Noveon Chemicals, Cleveland, Ohio.Other examples of thickeners include monoglycerides and fatty alcohols,fatty acid esters of alcohols having from about 3 to about 16 carbonatoms. Examples of suitable monoglycerides are glyceryl monostearate andglyceryl monopalmitate. Examples of fatty alcohols are cetyl alcohol andstearyl alcohol. Examples of suitable esters are myristyl stearate andcetyl stearate. The monoglyceride also functions as an auxiliaryemulsifier. Other emollients or oleaginous material which may beemployed include petrolatum, glyceryl monooleate, myristyl alcohol, andisopropyl palmitate. In one embodiment, the thickener is used incombination with an emulsifying agent.

When the topical formulations of the present invention contain at leastone viscosity increasing agent, the total amount of viscosity increasingagent present is from about 0.25% to about 5.0% by weight, preferablyfrom about 0.25% to about 1.0 wt %, and more preferably from about 0.4%to about 0.6% by weight.

The topical pharmaceutical compositions may also comprise adisintegrating agent including starch, e.g., a natural starch such ascorn starch or potato starch, a pregelatinized starch such as National1551 or Amijele®, or sodium starch glycolate such as Promogel® orExplotab®; a cellulose such as a wood product, microcrystallinecellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105,Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®,methylcellulose, croscarmellose, or a cross-linked cellulose, such ascross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose; a cross-linkedstarch such as sodium starch glycolate; a cross-linked polymer such ascrosspovidone; a cross-linked polyvinylpyrrolidone; alginate such asalginic acid or a salt of alginic acid such as sodium alginate; a claysuch as Veegum® HV (magnesium aluminum silicate); a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth; sodium starchglycolate; bentonite; a natural sponge; a surfactant; a resin such as acation-exchange resin; citrus pulp; sodium lauryl sulfate; sodium laurylsulfate in combination starch; and the like.

The topical pharmaceutical compositions may also comprise suitable nailpenetration enhancers. Examples of nail penetration enhancers includemercaptan compounds, sulfites and bisulfites, keratolytic agents andsurfactants. Nail penetration enhancers suitable for use in theinvention are described in greater detail in Malhotra et al., J. Pharm.Sci., 91:2, 312-323 (2002), which is incorporated herein by reference inits entirety.

The topical pharmaceutical compositions may also comprise ananti-foaming anti-whitening agent that increases the elegancy of thecream or lotion and inhibits the formation of a white soapy look uponrubbing the cream or lotion on the skin. An example of such materialincludes silicone fluid. Other anti-foaming agents include simethicone,polyglycol, and sorbitan sesquioleate.

The topical pharmaceutical compositions may also comprise a post-foamingagent. “Post-foaming” refers to a gel that remains a gel as it isexpelled from a container but foams up after it is spread over the skin.Post-foaming agents include saturated aliphatic hydrocarbons having from4-6 carbon atoms, such as butane, pentane and hexane (in particular isopentane and isobutene). Other suitable post-foaming agents includepartially, or wholly halogenated hydrocarbons, such astrichlorofluoroethane. Also, mixtures of aliphatic and halogenatedhydrocarbon propellants, or post-foaming agents can be used. Generallysuitable post-foaming agents are those substances that have a lowsolubility in water, for example less than about 20 cc of gas in 100grams of water at one atmosphere and 20.degree. C.

The topical pharmaceutical compositions may also comprise one or moresuitable solvents. The ability of any solid substance (solute) todissolve in any liquid substance (solvent) is dependent upon thephysical properties of the solute and the solvent. When solutes andsolvents have similar physical properties the solubility of the solutein the solvent will be the greatest. This gives rise to the traditionalunderstanding that “like dissolves like.” Solvents can be characterizedin one extreme as non-polar, lipophilic oils, while in the other extremeas polar hydrophilic solvents. Oily solvents dissolve other non-polarsubstances by Van der Wals interactions while water and otherhydrophilic solvents dissolve polar substances by ionic, dipole, orhydrogen bonding interactions. All solvents can be listed along acontinuum from the least polar, i.e. hydrocarbons such as decane, to themost polar solvent being water. A solute will have its greatestsolubility in solvents having equivalent polarity. Thus, for drugshaving minimal solubility in water, less polar solvents will provideimproved solubility with the solvent having polarity nearly equivalentto the solute providing maximum solubility. Most drugs have intermediatepolarity, and thus experience maximum solubility in solvents such aspropylene glycol or ethanol, which are significantly less polar thanwater. If the drug has greater solubility in propylene glycol (forexample 8% (w/w)) than in water (for example 0.1% (w/w)), then additionof water to propylene glycol should decrease the maximum amount of drugsolubility for the solvent mixture compared with pure propylene glycol.Addition of a poor solvent to an excellent solvent will decrease themaximum solubility for the blend compared with the maximum solubility inthe excellent solvent.

When compounds are incorporated into topical formulations theconcentration of active ingredient in the formulation may be limited bythe solubility of the active ingredient in the chosen solvent and/orcarrier. Non-lipophilic drugs typically display very low solubility inpharmaceutically acceptable solvents and/or carriers. For example, thesolubility of some compounds in the invention in water is less than0.00025% wt/wt. The solubility of the same compounds in the inventioncan be less than about 2% wt/wt in either propylene glycol or isopropylmyristate.

Examples of solubilizing excipients include polyethoxylated fatty acids,PEG-fatty acid diesters, PEG-fatty acid mono-ester and di-estermixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oiltransesterification products, polyglycerized fatty acids, propyleneglycol fatty acid esters, mixtures of propylene glycol esters-glycerolesters, mono- and diglycerides, sterol and sterol derivatives,polyethylene glycol sorbitan fatty acid esters, polyethylene glycolalkyl ethers, sugar esters, polyethylene glycol alkyl phenols,polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acidesters, lower alcohol fatty acid esters, ionic surfactants, tocopherolesters, and sterol esters. In one embodiment of the present invention,ethylhexyl hydroxystearate is the solvent used to dissolve the compoundsdescribed herein. In one embodiment of the present invention, diethyleneglycol monoethyl ether (DGME) is the solvent used to dissolve thecompounds described herein. In one embodiment of the present invention,diethylene glycol monoethyl ether (DGME) is the solvent used to dissolvea compound of the invention. The compounds in the invention useful inthe present formulation are believed to have a solubility of from about10% wt/wt to about 25% wt/wt in DGME. In another embodiment a DGME watercosolvent system is used to dissolve the compounds described herein. Inanother embodiment a DGME water cosolvent system is used to dissolve acompound of the invention. The solvent capacity of DGME drops when wateris added; however, the DGME/water cosolvent system can be designed tomaintain the desired concentration of from about 0.1% to about 5% wt/wtactive ingredient. Preferably the active ingredient is present fromabout 0.5% to about 3% wt/wt, and more preferably at about 1% wt/wt, inthe as-applied topical formulations. Because DGME is less volatile thanwater, as the topical formulation evaporates upon application, theactive agent becomes more soluble in the cream formulation. Thisincreased solubility reduces the likelihood of reduced bioavailabilitycaused by the drug precipitating on the surface of the skin, nail, hair,claw or hoof.

In one embodiment, the vehicle is lipophilic. Lipophilic materialsinclude oleaginous material such as petrolatum, mineral oil thickened orgelled with polyethylene, high molecular weight paraffin waxes, mono anddiglycerides of fatty acids gelled with high molecular weight fattyacids or polyamide complex of hydroxystearate, propylene glycolisostearate or isostearyl alcohol gelled with high molecular weightfatty acids, and mixtures thereof.

Liquid forms, such as lotions suitable for topical administration orsuitable for cosmetic application, may include a suitable aqueous ornonaqueous vehicle with buffers, suspending and dispensing agents,thickeners, penetration enhancers, and the like. Solid forms such ascreams or pastes or the like may include, for example, any of thefollowing ingredients, water, oil, alcohol or grease as a substrate withsurfactant, polymers such as polyethylene glycol, thickeners, solids andthe like. Liquid or solid formulations may include enhanced deliverytechnologies such as liposomes, microsomes, microsponges and the like.Liposomal formulations, which help allow compounds to enter the skin,are described in U.S. Pat. Nos. 5,169,637; 5,000,958; 5,049,388;4,975,282; 5,194,266; 5,023,087; 5,688,525; 5,874,104; 5,409,704;5,552,155; 5,356,633; 5,032,582; 4,994,213; and PCT Publication No. WO96/40061.

Additionally, the compounds can be delivered using a sustained-releasesystem, such as semipermeable matrices of solid hydrophobic polymerscontaining the therapeutic agent. Various sustained-release materialshave been established and are well known by those skilled in the art.Thus, at least two different dosage forms, each of which contains acompound of the invention, may be formulated for topical administrationby including such dosage forms in an oil-in-water emulsion, or awater-in-oil emulsion. In such a formulation, the delayed release dosageforms are in the continuous phase, and the delayed sustained releasedosage form is in a discontinuous phase. The formulation may also beproduced in a manner for delivery of three dosage forms as hereinabovedescribed. For example, there may be provided an oil-in-water-in-oilemulsion, with oil being a continuous phase that contains the thirddelayed sustained release component, water dispersed in the oilcontaining a first delayed release dosage form, and oil dispersed in thewater containing a second delayed release dosage form.

Topical treatment regimens according to the practice of this inventioncomprise applying the composition directly to the skin, nail, hair, clawor hoof at the application site, from one to several times daily.

Formulations of the present invention can be used to treat, ameliorateor prevent conditions or symptoms associated with bacterial infections,acne, inflammation and the like.

In an exemplary embodiment, the pharmaceutical formulation includes asimple solution. In an exemplary embodiment, the simple solutionincludes a polyether. In an exemplary embodiment, the polyether ispolyethylene glycol or polypropylene glycol. In an exemplary embodiment,the simple solution includes an alcohol. In an exemplary embodiment, thealcohol is methanol, ethanol, propanol, isopropanol or butanol. In anexemplary embodiment, the simple solution includes a polyether and analcohol. In another exemplary embodiment, the simple solution includes apolypropylene glycol and ethanol. In another exemplary embodiment, thesimple solution is a member selected from about 10% polypropylene glycoland about 90% ethanol; about 20% polypropylene glycol and about 80%ethanol; about 30% polypropylene glycol and about 70% ethanol; about 40%polypropylene glycol and about 60% ethanol; about 50% polypropyleneglycol and about 50% ethanol; about 60% polypropylene glycol and about40% ethanol; about 70% polypropylene glycol and about 30% ethanol; about80% polypropylene glycol and about 20% ethanol; about 90% polypropyleneglycol and about 10% ethanol.

In an exemplary embodiment, the simple solution includes acetone. In anexemplary embodiment, the simple solution includes acetone and analcohol. In an exemplary embodiment, the simple solution includesacetone and a member selected from methanol, ethanol, propanol,isopropanol or butanol. In an exemplary embodiment, the simple solutionincludes acetone, an alcohol and a polyether. In another exemplaryembodiment, the simple solution includes acetone, an alcohol and amember selected from polyethylene glycol and polypropylene glycol. In anexemplary embodiment, the simple solution includes acetone and ethanol.In another exemplary embodiment, the simple solution is a memberselected from about 10% acetone and about 90% ethanol; about 20% acetoneand about 80% ethanol; about 30% acetone and about 70% ethanol; about40% acetone and about 60% ethanol; about 50% acetone and about 50%ethanol; about 60% acetone and about 40% ethanol; about 70% acetone andabout 30% ethanol; about 80% acetone and about 20% ethanol; about 90%acetone and about 10% ethanol.

In an exemplary embodiment, the pharmaceutical formulation is a lacquer.

V. b) Additional Active Agents

The following are examples of the cosmetic and pharmaceutical agentsthat can be added to the topical pharmaceutical formulations of thepresent invention.

The following agents are known compounds and are readily availablecommercially. Anti-inflammatory agents include, but are not limited to,bisabolol, mentholatum, dapsone, aloe, hydrocortisone, and the like.

Vitamins include, but are not limited to, Vitamin B, Vitamin E, VitaminA, Vitamin D, and the like and vitamin derivatives such as tazarotene,calcipotriene, tretinoin, adapalene and the like.

Anti-aging agents include, but are not limited to, niacinamide, retinoland retinoid derivatives, AHA, Ascorbic acid, lipoic acid, coenzyme Q10, beta hydroxy acids, salicylic acid, copper binding peptides,dimethylaminoethyl (DAEA), and the like.

Sunscreens and or sunburn relief agents include, but are not limited to,PABA, jojoba, aloe, padimate-O, methoxycinnamates, proxamine HCl,lidocaine and the like. Sunless tanning agents include, but are notlimited to, dihydroxyacetone (DHA). Ultraviolet (UV) light blockersinclude, for example, amino benzoic acids, benzophenones, camphors,cinnamates, dibenzoyl methanes, salicylates, metal oxides, and mixturesthereof.

Psoriasis-treating agents and/or acne-treating agents include, but arenot limited to, salicylic acid, benzoyl peroxide, coal tar, seleniumsulfide, zinc oxide, pyrithione (zinc and/or sodium), tazarotene,calcipotriene, tretinoin, adapalene and the like.

Agents that are effective to control or modify keratinization, includingwithout limitation: tretinoin, tazarotene, and adapalene.

The compositions comprising an compound/active agent described herein,and optionally at least one of these additional agents, are to beadministered topically. In a primary application, this leads to thecompounds of the invention and any other active agent working upon andtreating the skin, nail, hair, claw or hoof. Alternatively, any one ofthe topically applied active agents may also be delivered systemicallyby transdermal routes.

In such compositions an additional cosmetically or pharmaceuticallyeffective agent, such as an anti-inflammatory agent, vitamin, anti-agingagent, sunscreen, and/or acne-treating agent, for example, is usually aminor component (from about 0.001% to about 20% by weight or preferablyfrom about 0.01% to about 10% by weight) with the remainder beingvarious vehicles or carriers and processing aids helpful for forming thedesired dosing form.

V. c) Testing

Preferred compounds for use in the present topical formulations willhave certain pharmacological properties. Such properties include, butare not limited to, low toxicity, low serum protein binding anddesirable in vitro and in vivo half-lives. Assays may be used to predictthese desirable pharmacological properties. Assays used to predictbioavailability include transport across human intestinal cellmonolayers, including Caco-2 cell monolayers. Serum protein binding maybe predicted from albumin binding assays. Such assays are described in areview by Oravcova et al. (1996, J. Chromat. B677: 1-27). Compoundhalf-life is inversely proportional to the frequency of dosage of acompound. In vitro half-lives of compounds may be predicted from assaysof microsomal half-life as described by Kuhnz and Gleschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD50 (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio between LD₅₀and ED₅₀. Compounds that exhibit high therapeutic indices are preferred.The data obtained from these cell culture assays and animal studies canbe used in formulating a range of dosage for use in humans. The dosageof such compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage can vary within this range depending upon the dosage formemployed and the route of administration utilized. The exactformulation, route of administration and dosage can be chosen by theindividual physician in view of the patient's condition. (See, e.g.Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch.1, p. 1).

V. d) Administration

For any compound used in the method of the invention, thetherapeutically effective dose can be estimated initially from cellculture assays, as disclosed herein. For example, a dose can beformulated in animal models to achieve a circulating concentration rangethat includes the EC₅₀ (effective dose for 50% increase) as determinedin cell culture, i.e., the concentration of the test compound whichachieves a half-maximal inhibition of bacterial cell growth. Suchinformation can be used to more accurately determine useful doses inhumans.

In general, the compounds prepared by the methods, and from theintermediates, described herein will be administered in atherapeutically or cosmetically effective amount by any of the acceptedmodes of administration for agents that serve similar utilities. It willbe understood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, and rate ofexcretion, drug combination, the severity of the particular diseaseundergoing therapy and the judgment of the prescribing physician. Thedrug can be administered from once or twice a day, or up to 3 or 4 timesa day.

Dosage amount and interval can be adjusted individually to provideplasma levels of the active moiety that are sufficient to maintainbacterial cell growth inhibitory effects. Usual patient dosages forsystemic administration range from 0.1 to 1000 mg/day, preferably, 1-500mg/day, more preferably 10-200 mg/day, even more preferably 100-200mg/day. Stated in terms of patient body surface areas, usual dosagesrange from 50-91 mg/m²/day.

The amount of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-10 wt %of the drug based on the total formulation, with the balance being oneor more suitable pharmaceutical excipients. Preferably, the compound ispresent at a level of about 0.1-3.0 wt %, more preferably, about 1.0 wt%.

In an exemplary embodiment, the pharmaceutical formulation is anointment, and comprises a compound of the invention. In an exemplaryembodiment, the pharmaceutical formulation is an ointment which includesC17. In an exemplary embodiment, the pharmaceutical formulation is anointment which includes C27.

In another exemplary embodiment, the pharmaceutical formulation includesC17 and at least one surfactant described herein. In another exemplaryembodiment, the pharmaceutical formulation includes C27 and at least onesurfactant described herein. In another exemplary embodiment, theformulation comprises a hydroxystearate. In another exemplaryembodiment, the hydroxystearate is a member selected from glycerylmonostearate, ethylhexyl hydroxystearate and octyl hydroxystearate.

In another exemplary embodiment, the pharmaceutical formulation includesC17 and an alcohol. In another exemplary embodiment, the pharmaceuticalformulation includes C27 and an alcohol. In another exemplaryembodiment, the alcohol is a long chain alcohol or a fatty alcohol. Inanother exemplary embodiment, the alcohol is a member selected frombenzyl alcohol, octyldodecanol, stearyl alcohol, cetyl alcohol, oleylalcohol. In an exemplary embodiment, the formulation comprises a memberselected from benzyl alcohol, octyl comprises at least one compoundwhich is a member selected from hydrocarbon oils, waxes, silicone, cetylalcohol, isopropyl myristate, stearyl alcohol, oleyl alcohol, ethylhexylhydroxystearate, octyl hydroxystearate, glycerin, other fatty alcoholshydroxystearate.

In another exemplary embodiment, the pharmaceutical formulationcomprises a compound of the invention and at least one emollientdescribed herein.

In another exemplary embodiment, the pharmaceutical formulation includesa compound of the invention, and petrolatum.

In an exemplary embodiment, the pharmaceutical formulation comprises C17and petrolatum. In an exemplary embodiment, the pharmaceuticalformulation comprises C27 and petrolatum. In an exemplary embodiment,the pharmaceutical formulation comprises C17 and a member selected fromhydrocarbon oils, waxes, silicone, cetyl alcohol, isopropyl myristate,stearyl alcohol, oleyl alcohol, ethylhexyl hydroxystearate, octylhydroxystearate, glycerin, other fatty alcohols hydroxystearate. In anexemplary embodiment, the pharmaceutical formulation comprises C27 and amember selected from hydrocarbon oils, waxes, silicone, cetyl alcohol,isopropyl myristate, stearyl alcohol, oleyl alcohol, ethylhexylhydroxystearate, octyl hydroxystearate, glycerin, other fatty alcoholshydroxystearate. In an exemplary embodiment, the pharmaceuticalformulation comprises C17 and ethylhexyl hydroxystearate and/or octylhydroxystearate. In an exemplary embodiment, the pharmaceuticalformulation comprises C27 and ethylhexyl hydroxystearate and/or octylhydroxystearate. In an exemplary embodiment, the pharmaceuticalformulation comprises C17, petrolatum and a member selected fromhydrocarbon oils, waxes, silicone, cetyl alcohol, isopropyl myristate,stearyl alcohol, oleyl alcohol, ethylhexyl hydroxystearate, octylhydroxystearate, glycerin, other fatty alcohols hydroxystearate. In anexemplary embodiment, the pharmaceutical formulation comprises C27,petrolatum and a member selected from hydrocarbon oils, waxes, silicone,cetyl alcohol, isopropyl myristate, stearyl alcohol, oleyl alcohol,ethylhexyl hydroxystearate, octyl hydroxystearate, glycerin, other fattyalcohols hydroxystearate. In an exemplary embodiment, the pharmaceuticalformulation comprises C17, petrolatum, oleyl alcohol and ethylhexylhydroxystearate. In an exemplary embodiment, the pharmaceuticalformulation comprises C27, petrolatum, oleyl alcohol and ethylhexylhydroxystearate.

In an exemplary embodiment, the pharmaceutical formulation is a cream,and comprises a compound of the invention. In an exemplary embodiment,the compound is C17. In an exemplary embodiment, the compound is C27.

In another exemplary embodiment, the pharmaceutical formulationcomprises a compound of the invention and a preservative. In anexemplary embodiment, the preservative is a member selected frombenzalkonium chloride, benzethonium, chlorohexidine, phenol, m-cresol,benzyl alcohol, methylparaben, propylparaben and other parabens,chlorobutanol, o-cresol, p-cresol, chlorocresol, phenylmercuric nitrate,thimerosal, benzoic acid, and various mixtures thereof. In an exemplaryembodiment, the compound is C17. In an exemplary embodiment, thecompound is C27. In an exemplary embodiment, the preservative is aparaben. In an exemplary embodiment, the preservative is a memberselected from methyl paraben and propyl paraben.

In another exemplary embodiment, the pharmaceutical formulationcomprises a compound of the invention and a chelating agent. In anotherexemplary embodiment, the pharmaceutical formulation comprises C17 and achelating agent. In another exemplary embodiment, the pharmaceuticalformulation comprises C27 and a chelating agent. In an exemplaryembodiment, the chelating agent is edetate sodium.

Exemplary embodiments are summarized herein below.

In an exemplary embodiment, the invention provides a compound having astructure according to the formula:

wherein R^(a) is a member selected from CN, C(O)NR¹R², C(O)OR³; whereinR³ is a member selected from H and substituted or unsubstituted alkyl, Xis a member selected from N, CH and CR^(b), R^(b) is a member selectedfrom halogen and substituted or unsubstituted alkyl, C(O)R⁴, C(O)OR⁴,OR⁴, NR⁴R⁵, wherein R¹, R², R⁴ and R⁵ are members independently selectedfrom H, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl, with the proviso that R¹ andR², together with the atoms to which they are attached, are optionallycombined to form a 4- to 8-membered substituted or unsubstitutedheterocycloalkyl ring; with the proviso that R⁴ and R⁵, together withthe atoms to which they are attached, are optionally combined to form a4- to 8-membered substituted or unsubstituted heterocycloalkyl ring, andsalts thereof.

In an exemplary embodiment, according to the above paragraph, R³ is amember selected from H and unsubstituted alkyl.

In an exemplary embodiment, according to any of the above paragraphs,the compound has a structure according to the formula:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a formula which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a formula which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a formula which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a formula which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a structure according to the formula:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a formula which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a formula which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a formula which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a formula which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a structure according to the formula:

the compound has a formula which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a formula which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a formula which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,the compound has a formula which is a member selected from:

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is a member selected from fluorine and chlorine.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is a member selected from OR⁴ and NR⁴R⁵.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, and R⁴ is a member selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, and R⁴ is a member selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl andsubstituted or unsubstituted cycloalkyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, and R⁴ is unsubstituted C₁-C₆ alkyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, and R⁴ is unsubstituted cycloalkyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, and R⁴ is alkyl, substituted with a member selected fromsubstituted or unsubstituted C₁-C₆ alkoxy.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, and R⁴ is alkyl, substituted with at least one halogen.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, and R⁴ is alkyl, substituted with at least one oxo moiety.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, and R⁴ is a member selected from —CH₃, —CH₂CH₃,—(CH₂)₂CH₃, —CH(CH₃)₂, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂(OH), —CH₂CH₂(OCH₃),—CH₂CH₂(OC(CH₃)₂), —C(O)CH₃, —CH₂CH₂OC(O)CH₃, —CH₂C(O)OCH₂CH₃,—CH₂C(O)OC(CH₃)₃, —(CH₂)₃C(O)CH₃, —CH₂C(O)OC(CH₃)₃, cyclopentyl,cyclohexyl

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, wherein R⁴ is alkyl is optionally substituted with atleast one halogen, hydroxyl, ether, carboxy or ester moiety.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, wherein R⁴ is unsubstituted alkyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, wherein R⁴ is unsubstituted C₁ or C₂ or C₃ alkyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, wherein R⁴ is unsubstituted C₄ or C₅ or C₆ alkyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, wherein R⁴ is methyl or ethyl or propyl or isopropyl orisobutyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is —O(CH₂)_(m1)OC(O)R^(4d), wherein m1 is a number selected from 1or 2 or 3 or 4 or 5 or 6 and R^(4d) is unsubstituted alkyl. In anexemplary embodiment, m1 is 1 or 2 or 3. In an exemplary embodiment, m1is 2. In an exemplary embodiment, R^(4d) is unsubstituted C₁ or C₂ or C₃alkyl. In an exemplary embodiment, R^(4d) is unsubstituted C₄ or C₅ orC₆ alkyl. In an exemplary embodiment, R^(4d) is methyl. In an exemplaryembodiment, R^(b) is —O(CH₂)₂OC(O)CH₃.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is —O(CH₂)_(m1)C(O)R^(4d), wherein m1 is a number selected from 1or 2 or 3 or 4 or 5 or 6 and R^(4d) is unsubstituted alkyl. In anexemplary embodiment, m1 is 2 or 3 or 4. In an exemplary embodiment, m1is 3. In an exemplary embodiment, R^(4d) is unsubstituted C₁ or C₂ or C₃alkyl. In an exemplary embodiment, R^(4d) is unsubstituted C₄ or C₅ orC₆ alkyl. In an exemplary embodiment, R^(4d) is methyl. In an exemplaryembodiment, R^(b) is —O(CH₂)₃C(O)CH₃.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is —O(CH₂)_(m1)C(O)OR^(4d), wherein m1 is a number selected from 1or 2 or 3 or 4 or 5 or 6 and R^(4d) is H or unsubstituted alkyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is —OCH₂C(O)OR^(4d), wherein R^(4d) is as described herein.

In an exemplary embodiment, according to any of the above paragraphs,R^(4d) is H or methyl or ethyl or t-butyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is —O(CH₂)C(O)OCH₂CH₃ or —O(CH₂)C(O)OH or —O(CH₂)C(O)OC(CH₃)₃.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, wherein R⁴ is alkyl substituted with a substituted orunsubstituted amino.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is —O(CH₂)_(m2)C(O)NR^(4e)R^(4f), wherein m2 is a number selectedfrom 1 or 2 or 3 or 4 or 5 or 6, and R^(4e) and R^(4f) are independentlyselected from H or unsubstituted alkyl, or R^(4e) and R^(4f), togetherwith the nitrogen to which they are attached, are optionally joined toform a substituted or unsubstituted 4 to 8 membered ring.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, wherein R⁴ is substituted or unsubstituted cycloalkyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is OR⁴, wherein R⁴ is unsubstituted cycloalkyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is —O(CH₂)_(m5)OR³⁰, wherein m5 is 1 or 2 or 3 or 4 or 5 or 6 andR³⁰ is H or unsubstituted alkyl or unsubstituted tetrahydropyran.

In an exemplary embodiment, according to any of the above paragraphs, Xis N.

In an exemplary embodiment, according to any of the above paragraphs, Xis CH.

In an exemplary embodiment, according to any of the above paragraphs, Xis CR^(b).

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is NR⁴R⁵, wherein R⁴ and R⁵ are members independently selectedfrom H, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is NR⁴R⁵, wherein R⁴ is H or unsubstituted alkyl; and R⁵ isunsubstituted alkyl or alkyl substituted with a member selected fromhydroxyl, phenyl, unsubstituted alkoxy and alkoxy substituted with aphenyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is NR⁴R⁵.

In an exemplary embodiment, according to any of the above paragraphs, R⁴is a member selected from H or CH₃.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is NR⁴R⁵ wherein R⁴ and R⁵ are each members independently selectedfrom substituted or unsubstituted alkyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is NR⁴R⁵, wherein R⁵ is alkyl, substituted with a member selectedfrom OH, unsubstituted arylalkoxy, unsubstituted alkoxy, andunsubstituted aryl. In an exemplary embodiment, R^(b) is NR⁴R⁵, whereinR⁵ is —(CH₂)_(m8)Ph.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is NR⁴R⁵, wherein R⁵ is —(CH₂)_(m8)OR²⁶, wherein m8 is a numberselected from 1 or 2 or 3 or 4 or 5 or 6 and R²⁶ is a member selectedfrom H, unsubstituted or arylsubstituted C₁ or C₂ or C₃ or C₄ or C₅ orC₆ alkyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is NR⁴R⁵, wherein R⁵ is —(CH₂)_(m8)O(CH₂)_(m9)Ph, wherein m8 andm9 are each independently selected from 1 or 2 or 3.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl; and R⁵ is substitutedor unsubstituted alkyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl; and R⁵ is alkyl,substituted with a member selected from substituted or unsubstitutedalkoxy and hydroxyl.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl; and R⁵ is alkyl,substituted with unsubstituted alkoxy.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is a member selected from N(CH₃)₂, N(CH₃)(CH₂CH₂(OCH₃)),N(CH₃)(CH₂CH₂OH), NH₂, NHCH₃, NH(CH₂CH₂(OCH₃)), NH(CH₂CH₂(OCH₂Ph),NH(CH₂Ph), NH(C(CH₃)₃) and NH(CH₂CH₂OH).

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is NR⁴R⁵, wherein R⁴ and R⁵, together with the nitrogen to whichthey are attached, are combined to form a 4- to 8-membered substitutedor unsubstituted heterocycloalkyl ring.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is NR⁴R⁵, wherein R⁴ and R⁵, together with the nitrogen to whichthey are attached, are combined to form a 5- or 6-membered substitutedor unsubstituted heterocycloalkyl ring.

In an exemplary embodiment, according to any of the above paragraphs,R^(b) is a member selected from:

In an exemplary embodiment, the invention provides a pharmaceuticalformulation comprising: (a) a compound according to any of the aboveparagraphs; and (b) a pharmaceutically acceptable excipient.

In an exemplary embodiment, according to any of the above paragraphs,the formulation is in a unit dosage form.

In an exemplary embodiment, according to any of the above paragraphs,the formulation is for oral or topical use.

In an exemplary embodiment, the invention provides a method ofdecreasing the release of a cytokine or a chemokine, the methodcomprising: contacting a cell with a compound according to any of theabove paragraphs or a pharmaceutically acceptable salt thereof, whereinthe release of the cytokine or chemokine by the cell is decreased.

In an exemplary embodiment, according to any of the above paragraphs,the cytokine is a member selected from IL-1α, IL-1β, IL-2, IL-3, IL-6,IL-7, IL-9, IL-12, IL-17, IL-18, IL-23, TNF-α, LT, LIF, Oncostatin,IFNα, IFNβ and IFN-γ.

In an exemplary embodiment, according to any of the above paragraphs,the cytokine is a member selected from IL-1β, IL-2, IL-4, IL-5, IL-6,IL-8, IL-10, IL-12, IL-23, TNF-α and IFN-γ.

In an exemplary embodiment, according to any of the above paragraphs,the cytokine is a member selected from IL-2, IL-5, IL-10, IL-12, IL-23,TNF-α and IFN-γ.

In an exemplary embodiment, according to any of the above paragraphs,the chemokine is a member selected from IL-8, Gro-α, MIP-1, MCP-1, PGE2,ENA-78, and RANTES.

In an exemplary embodiment, the invention provides a method of treatinga condition, in an animal, the method comprising administering to theanimal a therapeutically effective amount of a compound according to anyof the above paragraphs, or a pharmaceutically acceptable salt thereof,thereby treating the condition.

In an exemplary embodiment, according to any of the above paragraphs,the condition is a member selected from arthritis, rheumatoid arthritis,an inflammatory bowel disease, psoriasis, a pulmonary disease, multiplesclerosis, a neurodegenerative disorder, congestive heart failure,stroke, aortic valve stenosis, kidney failure, lupus, pancreatitis,allergy, fibrosis, anemia, atherosclerosis, a metabolic disease, a bonedisease, a cardiovascular disease, a chemotherapy/radiation relatedcomplication, diabetes type I, diabetes type II, a liver disease, agastrointestinal disorder, an ophthamological disease, allergicconjunctivitis, diabetic retinopathy, Sjogren's syndrome, uvetitis, apulmonary disorder, a renal disease, dermatitis, HIV-related cachexia,cerebral malaria, ankylosing spondolytis, leprosy, anemia andfibromyalgia.

In an exemplary embodiment, according to any of the above paragraphs,the condition is a member selected from psoriasis, atopic dermatitis,rheumatoid arthritis, an inflammatory bowel disease, asthma and chronicobstructive pulmonary disease.

In an exemplary embodiment, according to any of the above paragraphs,the condition is psoriasis, said psoriasis is a member selected fromplaque psoriasis, flexural psoriasis, Guttate psoriasis, pustularpsoriasis, nail psoriasis and erythrodermic psoriasis.

In an exemplary embodiment, according to any of the above paragraphs,the psoriasis is a member selected from plaque psoriasis and nailpsoriasis.

In an exemplary embodiment, according to any of the above paragraphs,the animal is a human.

In an exemplary embodiment, according to any of the above paragraphs,the animal is in need of treatment.

In an exemplary embodiment, according to any of the above paragraphs,the animal is a human.

In an exemplary embodiment, according to any of the above paragraphs,the animal is not already in need of treatment by the compound.

In an exemplary embodiment, the invention provides a method ofinhibiting a phosphodiesterase (PDE), the method comprising: contactingthe phosphodiesterase with a compound according to any of the aboveparagraphs, or a pharmaceutically acceptable salt thereof, therebyinhibiting the phosphodiesterase.

In an exemplary embodiment, according to any of the above paragraphs,the phosphodiesterase is a member selected from phosphodiesterase4(PDE4) and phosphodiesterase7 (PDE7).

The invention is further illustrated by the Examples that follow. TheExamples are not intended to define or limit the scope of the invention.

EXAMPLES

Proton NMR are recorded on Varian AS 300 (300 MHz) or AS400 (400 MHz)spectrometer and chemical shifts are reported as δ (ppm) down field fromtetramethylsilane. Mass spectra are determined on Agilent 1200 seriesplus 6120 Quadrupole LC/MS, Micromass Quattro II or Waters MS consistingof an Alliance 2795 (LC) and Waters Micromass ZQ detector. The massspectrometer was equipped with an electrospray ion source (ES) operatedin a positive or negative mode.

The following abbreviations have been used: aqueous is aq.;O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate is HATU;N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride m-CPBA3-chloroperoxybenzoic acid is EDCI; equivalent is eq.; diisopropylazodicarboxylate is DIAD; N,N-dimethylformamide is DMF;dimethylsulfoxide is DMSO; acetic acid is HOAc; sodium cyanoborohydrideis NaCNBH₃; room temperature is r.t.; overnight is O/N; tetrahydrofuranis THF; Di-tert-butyl dicarbonate is Boc₂O; methanol is MeOH; ethanol isEtOH; trifluoroacetic acid is TFA; Diisopropylethylamine is DIPEA;1-propanol is PrOH; 2-propanol is iPrOH and melting point is mp.

All solvents used were commercially available and were used withoutfurther purification. Reactions were typically run using anhydroussolvents under an inert atmosphere of nitrogen.

Compounds are named either manually or by using ChemDraw, or using theircatalogue name if commercially available.

HPLC analyses were performed on a Water 600 Controller system with aWaters 717 Plus Autosampler and a Waters 2996 Photodiode Array Detector.The column used was an ACE C₁₈, 5 μm, 4.6×150 mm. A linear gradient wasapplied, starting at 95% A (A: 0.1% H₃PO₄ in water) and ending at 90% B(B: MeCN) over 6 min and then maintained at 90% B until the 10 min mark.The column is then re-equilibrated over 3 min to 95:5 with a total runtime of 20 min. The column temperature was at ambient temperature withthe flow rate of 1.0 mL/min. The Diode Array Detector was scanned from200-400 nm.

Thin layer chromatography (TLC) was performed on Alugram® (Silica gel 60F₂₅₄) from Mancherey-Nagel and UV was typically used to visualize thespots. Additional visualization methods were also employed in somecases. In these cases the TLC plate was developed with iodine (generatedby adding approximately 1 g of I₂ to 10 g silica gel and thoroughlymixing), vanillin (generated by dissolving about 1 g vanillin in 100 mL10% H₂SO₄), ninhydrin (available commercially from Aldrich), or MagicStain (generated by thoroughly mixing 25 g (NH₄)₆Mo₇O₂₄.4H₂O, 5 g(NH₄)₂Ce(IV)(NO₃)₆ in 450 mL water and 50 mL concentrated H₂SO₄) tovisualize the compound. Flash chromatography was preformed usingtypically 40-63 μm (230-400 mesh) silica gel from Silicycle followinganalogous techniques to those disclosed in Still, W. C.; Kahn, M.; andMitra, M. Journal of Organic Chemistry, 1978, 43, 2923-2925. Typicalsolvents used for flash chromatography or thin layer chromatography weremixtures of chloroform/methanol, dichloromethane/methanol, ethylacetate/methanol and hexanes/ethyl acetate. Reverse phase columnchromatography were performed on a Biotage using a Biotage C₁₈cartridges and a water/methanol gradient (typically eluting from 5%MeOH/H₂O to 90% MeOH/H₂O).

Preparative chromatography was performed on either a Waters Prep LC 4000System using a Waters 2487 Diode Array or on a Waters LC Module 1 plus.The column used was a Waters XTerra Prep C₁₈, 5 μm, 30×100 mm orPhenomenex Luna C₁₈, 5 μm, 21.6×250 mm or Phenomenex Gemini C₁₈, 5 μm,100×30 mm. Narrow gradients with acetonitrile/water, with the watercontaining either 0.1% trifluoroacetic acid or 0.1% acetic acid, wereused to elute the compound at a flow rate of approximately 20 mL/min anda total run time between 20-30 min.

Example 1 Preparation of 3 from 1 1.1 Reduction of Carboxylic Acid

To a solution of 1 (23.3 mmol) in anhydrous THF (70 mL) under nitrogenwas added dropwise a BH₃ THF solution (1.0 M, 55 mL, 55 mmol) at 0° C.and the reaction mixture was stirred overnight at room temperature. Thenthe mixture was cooled again with ice bath and MeOH (20 mL) was addeddropwise to decompose excess BH₃. The resulting mixture was stirreduntil no bubble was released and then 10% NaOH (10 mL) was added. Themixture was concentrated and the residue was mixed with water (200 mL)and extracted with EtOAc. The residue from rotary evaporation waspurified by flash column chromatography over silica gel to give 20.7mmol of 3.

1.2 Results

Exemplary compounds of structure 3 prepared by the method above include:1.2.a 2-Bromo-5-chlorobenzyl Alcohol; 1.2.b 2-Bromo-5-methoxybenzylAlcohol.

Example 2 Preparation of 3 from 2 2.1. Reduction of Aldehyde

To a solution of 2 (Z=H, 10.7 mmol) in methanol (30 mL) was added sodiumborohydride (5.40 mol), and the mixture was stirred at room temperaturefor 1 h. Water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with brine and dried on anhydroussodium sulfate. The solvent was removed under reduced pressure to afford9.9 mmol of 3.

Exemplary compounds of structure 3 prepared by the method include: 2.2.a2-Bromo-5-(4-cyanophenoxy)benzyl Alcohol; 2.2.b2-Bromo-4-(4-cyanophenoxy)benzyl Alcohol; 2.2.c5-(4-Cyanophenoxy)-1-Indanol; 2.2.d2-Bromo-5-(tert-butyldimethylsiloxy)benzyl Alcohol.

Additional examples of compounds which can be produced by this methodinclude 2-bromo-4-(3-cyanophenoxy)benzyl alcohol;2-bromo-4-(4-chlorophenoxy)benzyl alcohol; 2-bromo-4-phenoxybenzylalcohol; 2-bromo-5-(3,4-dicyanophenoxy)benzyl alcohol;2-(2-bromo-5-fluorophenyl)ethyl alcohol; 2-bromo-5-fluorobenzyl alcohol;and 1-bromo-2-naphthalenemethanol.

Example 3 Preparation of 4 from 3 3.1 Protective Alkylation

Compound 3 (20.7 mmol) was dissolved in CH₂Cl₂ (150 mL) and cooled to 0°C. with ice bath. To this solution under nitrogen were added in sequenceN,N-di-isopropyl ethyl amine (5.4 mL, 31.02 mmol, 1.5 eq) andchloromethyl methyl ether (2 mL, 25.85 mmol, 1.25 eq). The reactionmixture was stirred overnight at room temperature and washed withNaHCO₃-saturated water and then NaCl-saturated water. The residue afterrotary evaporation was purified by flash column chromatography oversilica gel to give 17.6 mmol of 4.

3.2 Results

Exemplary compounds of structure 4 prepared by the method above include:3.2.a 2-Bromo-5-chloro-1-(methoxymethoxymethyl)benzene; 3.2.b2-Bromo-5-fluoro-1-[1-(methoxymethoxy)ethyl]benzene; 3.2.c2-Bromo-5-fluoro-1-[2-(methoxymethoxy)ethyl]benzene; 3.2.d2-Bromo-4,5-difluoro-1-(methoxymethoxymethyl)benzene; 3.2.e2-Bromo-5-cyano-1-(methoxymethoxymethyl)benzene; 3.2.f2-Bromo-5-methoxy-1-(methoxymethoxymethyl)benzene; 3.2.g1-Benzyl-1-(2-bromophenyl)-1-(methoxymethoxy)ethane; 3.2.h2-Bromo-6-fluoro-1-(methoxymethoxymethyl)benzene; 3.2.i2-Bromo-4-(4-cyanophenoxy)-1-(methoxymethoxymethyl)benzene; 3.2.j2-Bromo-5-(tert-butyldimethylsiloxy)-1-(methoxymethoxymethyl)benzene;3.2.k 2-Bromo-5-(2-cyanophenoxy)-1-(methoxymethoxymethyl)benzene; 3.2.l2-Bromo-5-phenoxy-1-(methoxymethoxymethyl)benzene.

Additional examples of compounds which can be produced by this methodinclude 2-bromo-1-(methoxymethoxymethyl)benzene;2-bromo-5-methyl-1-(methoxymethoxymethyl)benzene;2-bromo-5-(methoxymethoxymethyl)-1-(methoxymethoxymethyl)benzene;2-bromo-5-fluoro-1-(methoxymethoxymethyl)benzene;1-bromo-2-(methoxymethoxymethyl)naphthalene;2-bromo-4-fluoro-1-(methoxymethoxymethyl)benzene;2-phenyl-1-(2-bromophenyl)-1-(methoxymethoxy)ethane;2-bromo-5-(4-cyanophenoxy)-1-(methoxymethoxy methyl)benzene;2-bromo-4-(3-cyanophenoxy)-1-(methoxymethoxymethyl)benzene;2-bromo-4-(4-chlorophenoxy)-1-(methoxymethoxymethyl)benzene;2-bromo-4-phenoxy-1-(methoxymethoxymethyl)benzene;2-bromo-5-(3,4-dicyanophenoxy)-1-(methoxymethoxymethyl)benzene.

Example 4 Preparation of I from 4 via 5 4.1 Metallation and Boronylation

To a solution of 4 (17.3 mmol) in anhydrous THF (80 mL) at −78° C. undernitrogen was added dropwise tert-BuLi or n-BuLi (11.7 mL) and thesolution became brown colored. Then, B(OMe)₃ (1.93 mL, 17.3 mmol) wasinjected in one portion and the cooling bath was removed. The mixturewas warmed gradually with stirring for 30 min and then stirred with awater bath for 2 h. After addition of 6N HCl (6 mL), the mixture wasstirred overnight at room temperature and about 50% hydrolysis hashappened as shown by TLC analysis. The solution was rotary evaporatedand the residue was dissolved in MeOH (50 mL) and 6N HCl (4 mL). Thesolution was refluxed for 1 h and the hydrolysis was completed asindicated by TLC analysis. Rotary evaporation gave a residue which wasdissolved in EtOAc, washed with water, dried and then evaporated. Thecrude product was purified by flash column chromatography over silicagel to provide a solid with 80% purity. The solid was further purifiedby washing with hexane to afford 7.2 mmol of I.

4.2 Results

Analytical data for exemplary compounds of structure I prepared by themethod above include: 4.2.a5-Chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C1); 4.2.b1,3-Dihydro-1-hydroxy-2,1-benzoxaborole (C2); 4.2.c5-Fluoro-1,3-dihydro-1-hydroxy-3-methyl-2,1-benzoxaborole (C3); 4.2.d6-Fluoro-1-hydroxy-1,2,3,4-tetrahydro-2,1-benzoxaborine (C4); 4.2.e5,6-Difluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C5); 4.2.f5-Cyano-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C6); 4.2.g1,3-Dihydro-1-hydroxy-5-methoxy-2,1-benzoxaborole (C7); 4.2.h1,3-Dihydro-1-hydroxy-5-methyl-2,1-benzoxaborole (C8); 4.2.i1,3-Dihydro-1-hydroxy-5-hydroxymethyl-2,1-benzoxaborole (C9); 4.2.k1,3-Dihydro-2-oxa-1-cyclopenta[{acute over (α)}]naphthalene (C11); 4.2.l7-Hydroxy-2,1-oxaborolano[5,4-c]pyridine (C12); 4.2.m1,3-Dihydro-6-fluoro-1-hydroxy-2,1-benzoxaborole (C13); 4.2.n3-Benzyl-1,3-dihydro-1-hydroxy-3-methyl-2,1-benzoxaborole (C14); 4.2.o3-Benzyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C15); 4.2.p1,3-Dihydro-4-fluoro-1-hydroxy-2,1-benzoxaborole (C16); 4.2.q5-(4-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C17); 4.2.r6-(4-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C18); 4.2.s6-(3-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C19); 4.2.t6-(4-Chlorophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C20); 4.2.u6-Phenoxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C21); 4.2.v5-(4-Cyanobenzyloxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C22);4.2.w 5-(2-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C23);4.2.x 5-Phenoxy-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C24); 4.2.y5-[4-(N,N-Diethylcarbamoyl)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(C25); 4.2.z1,3-Dihydro-1-hydroxy-5-[4-(morpholinocarbonyl)phenoxy]-2,1-benzoxaborole(C26); 4.2.aa5-(3,4-Dicyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C27);4.2.ab 6-Phenylthio-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C28);4.2.ac6-(4-trifluoromethoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(C29); 4.2.ad5-(N-Methyl-N-phenylsulfonylamino)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(C30); 4.2.ae6-(4-Methoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C31);4.2.af 6-(4-Methoxyphenylthio)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(C32); 4.2.ag6-(4-Methoxyphenylsulfonyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(C33); 4.2.ah6-(4-Methoxyphenylsulfinyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(C34); 4.2.ai 5-Trifluoromethyl-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(C35) and 4.2.aj4-(4-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C36).

For coupling reaction between 4-fluorobenzonitrile and substitutedphenol to give starting material 2, see Igarashi, S.; et al. Chemical &Pharmaceutical Bulletin (2000), 48(11), 1689-1697.

7-(4-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C100)

For coupling reaction between 4-fluorobenzonitrile and substitutedphenol to give starting material 2, see Igarashi, S.; et al. Chemical &Pharmaceutical Bulletin (2000), 48(11), 1689-1697.

4.2.ak 5-(3-Cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (C37)

For coupling between 3-fluorobenzonitrile and substituted phenol to givestarting material 2: Li, F. et al., Organic Letters (2003), 5 (12),2169-2171.

4.2.al 5-(4-Carboxyphenoxy)-1-hydroxy-2,1-benzoxaborole (C38)

To a solution of 5-(4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole obtainedin C17 (430 mg, 1.71 mmol) in ethanol (10 mL) was added 6 mol/L sodiumhydroxide (2 mL), and the mixture was refluxed for 3 hours. Hydrochloricacid (6 mol/L, 3 mL) was added, and the mixture was extracted with ethylacetate. The organic layer was washed with brine and dried on anhydroussodium sulfate. The solvent was removed under reduced pressure, and theresidue was purified by silica gel column chromatography (ethyl acetate)followed by trituration with diisopropyl ether to give the targetcompound (37 mg, 8%).

4.2.am 1-Hydroxy-5-[4-(tetrazole-1-yl)phenoxy]-2,1-benzoxaborole (C39)

A mixture of 5-(4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole (200 mg,0.797 mmol), sodium azide (103 mg, 1.59 mmol), and ammonium chloride (85mg, 1.6 mmol) in N,N-dimethylformamide (5 mL) was stirred at 80° C. fortwo days. Water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with water and brine, and dried onanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate) followed by trituration with ethylacetate to give the target compound (55 mg, 23%).

Example 5 Preparation of I from 2 via 6 5.1 Catalytic Boronylation,Reduction and Cyclization

A mixture of 2 (10.0 mmol), bis(pinacolato)diboron (2.79 g, 11.0 mmol),PdCl₂(dppf) (250 mg, 3 mol %), and potassium acetate (2.94 g, 30.0 mmol)in 1,4-dioxane (40 mL) was stirred at 80° C. for overnight. Water wasadded, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine and dried on anhydrous sodium sulfate. Thesolvent was removed under reduced pressure. The crude product wasdissolved in tetrahydrofuran (80 mL), then sodium periodate (5.56 g,26.0 mmol) was added. After stirring at room temperature for 30 min, 2NHCl (10 mL) was added, and the mixture was stirred at room temperaturefor overnight. Water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with brine and dried on anhydroussodium sulfate. The solvent was removed under reduced pressure, and theresidue was treated with ether to afford 6.3 mmol of the correspondingboronic acid. To the solution of the obtained boronic acid (0.595 mmol)in methanol (5 mL) was added sodium borohydride (11 mg, 0.30 mmol), andthe mixture was stirred at room temperature for 1 h. Water was added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with brine and dried on anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was purified by silicagel column chromatography to give 0.217 mmol of I.

Example 6 Preparation of I from 3 6.1 One-Pot Boronylation andCyclization

To a solution of 3 (4.88 mmol) and triisopropyl borate (1.35 mL, 5.86mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (1.6 mol/L inhexanes; 6.7 mL, 10.7 mmol) dropwise over 15 min at −78° C. undernitrogen atmosphere, and the mixture was stirred for 2 h while allowingto warm to room temperature. The reaction was quenched with 2N HCl, andextracted with ethyl acetate. The organic layer was washed with brineand dried on anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was purified by silica gel columnchromatography and treated with pentane to give 0.41 mmol of I.

Example 7 Preparation of I from 3

7.1 One-Pot Boronylation and Cyclization with Distillation

To a solution of 3 (4.88 mmol) in toluene (20 mL) was added triisopropylborate (2.2 mL, 9.8 mmol), and the mixture was heated at reflux for 1 h.The solvent, the generated isopropyl alcohol and excess triisopropylborate were removed under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL) and cooled to −78° C. n-Butyllithium (3.2 mL,5.1 mmol) was added dropwise over 10 min, and the mixture was stirredfor 1 h while allowing to warm to room temperature. The reaction wasquenched with 2N HCl, and extracted with ethyl acetate. The organiclayer was washed with brine and dried on anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, and the residue was purifiedby silica gel column chromatography to give 1.54 mmol of I.

Example 8 Preparation of 8 from 7 8.1 Bromination

To a solution of 7 (49.5 mmol) in carbon tetrachloride (200 mL) wereadded N-bromosuccinimide (8.81 g, 49.5 mmol) and N,N-azoisobutylonitrile(414 mg, 5 mol %), and the mixture was heated at reflux for 3 h. Waterwas added, and the mixture was extracted with chloroform. The organiclayer was washed with brine and dried on anhydrous sodium sulfate. Thesolvent was removed under reduced pressure to give the crudemethyl-brominated intermediate 8.

Example 9 Preparation of 3 from 8 9.1 Hydroxylation

To crude 8 (49.5 mmol) were added dimethylformamide (150 mL) and sodiumacetate (20.5 g, 250 mmol), and the mixture was stirred at 80° C. forovernight. Water was added, and the mixture was extracted with ether.The organic layer was washed with water and brine, and dried onanhydrous sodium sulfate. The solvent was removed under reducedpressure. To the residue was added methanol (150 mL) and 1N sodiumhydroxide (50 mL), and the mixture was stirred at room temperature for 1h. The reaction mixture was concentrated to about a third of volumeunder reduced pressure. Water and hydrochloric acid were added, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and brine, and dried on anhydrous sodium sulfate. The solventwas removed under reduced pressure, and the residue was purified bysilica gel column chromatography followed by trituration withdichloromethane to give 21.8 mmol of 3.

9.2 Results

Exemplary compounds of structure 3 prepared by the method above include:9.2.a 2-Bromo-5-cyanobenzyl Alcohol.

Additional examples of compounds which can be produced by this methodinclude 2-bromo-5-(4-cyanophenoxy)benzyl alcohol.

Example 10 Preparation of 9 from 2 10.1 Reaction

A mixture of 2 (20.0 mmol), (methoxymethyl)triphenylphosphonium chloride(8.49 g, 24.0 mmol), and potassium tert-butoxide (2.83 g, 24.0 mol) inN,N-dimethylformamide (50 mL) was stirred at room temperature forovernight. The reaction was quenched with 6 N HCl, and the mixture wasextracted with ethyl acetate. The organic layer was washed with water(×2) and brine, and dried on anhydrous sodium sulfate. The solvent wasremoved under reduced. To the residue were added tetrahydrofuran (60 mL)and 6 N HCl, and the mixture was heated at reflux for 8 h. Water wasadded, and the mixture was extracted with ether. The organic layer waswashed with brine and dried on anhydrous sodium sulfate. The solvent wasremoved under reduced pressure to afford 16.6 mmol of 9.

Example 11 Preparation Method of Step 13 11.1 Reaction

A solution of I in an appropriate alcohol solvent (R¹—OH) was refluxedunder nitrogen atmosphere and then distilled to remove the alcohol togive the corresponding ester.

Example 12 Preparation of Ib from Ia 12.1 Reaction

To a solution of Ia in toluene was added amino alcohol and theparticipated solid was collected to give Ib.

12.2 Results

(500 mg, 3.3 mmol) was dissolved in toluene (37 mL) at 80° C. andethanolamine (0.20 mL, 3.3 mmol) was added. The mixture was cooled toroom temperature, then ice bath, and filtered to give C38 as a whitepowder (600.5 mg, 94%).

Example 13 5-(4-Carboxyphenoxy)-1-hydroxy-2,1-benzoxaborole (C38)

To a solution of 5-(4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole obtainedin C17 (430 mg, 1.71 mmol) in ethanol (10 mL) was added 6 mol/L sodiumhydroxide (2 mL), and the mixture was refluxed for 3 hours. Hydrochloricacid (6 mol/L, 3 mL) was added, and the mixture was extracted with ethylacetate. The organic layer was washed with brine and dried on anhydroussodium sulfate. The solvent was removed under reduced pressure, and theresidue was purified by silica gel column chromatography (ethyl acetate)followed by trituration with diisopropyl ether to give the targetcompound (37 mg, 8%).

Example 14 1-Hydroxy-5-[4-(tetrazole-1-yl)phenoxy]-2,1-benzoxaborole(C39)

A mixture of 5-(4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole (200 mg,0.797 mmol), sodium azide (103 mg, 1.59 mmol), and ammonium chloride (85mg, 1.6 mmol) in N,N-dimethylformamide (5 mL) was stirred at 80° C. fortwo days. Water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with water and brine, and dried onanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate) followed by trituration with ethylacetate to give the target compound (55 mg, 23%).

Example 15 4-(4-Cyanophenoxy)phenylboronic acid (C97)

(a) (4-cyanophenyl)(4-bromophenyl)ether. Under nitrogen, the mixture of4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirredat 100° C. for 16 h and then filtered. After rotary evaporation, theresidue was dissolved in ethyl acetate and washed with 1N NaOH solutionto remove unreacted phenol. The organic solution was dried and passedthrough a short silica gel column to remove the color and minor phenolimpurity. Evaporation of the solution gave(4-cyanophenyl)(4-bromophenyl)ether (13.82 g, yield 87.2%) as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d,2H) and 7.10 (d, 2H) ppm.

(b) 4-(4-cyanophenoxy)phenylboronic acid. The procedure described inExample 2d was used for the synthesis of 4-(4-cyanophenoxy)phenylboronicacid using (4-cyanophenyl)(4-bromophenyl)ether as starting material. Thetitle compound was obtained as a white solid. M.p. 194-198° C. MS:m/z=239 (M+), 240 (M+1) (ESI+) and m/z=238 (M−1) (ESI−). HPLC: 95.3%purity at 254 nm and 92.1% at 220 nm. ¹H NMR (300 MHz, DMSO-d₆+D₂O): δ7.83-7.76 (m, 4H), 7.07 (d, 2H) and 7.04 (d, 2H) ppm.

Example 16 3-(4-Cyanophenoxy)phenylboronic acid (C98)

By following the procedures described for the synthesis of C21, thetitle compound was acquired from (4-cyanophenyl)(3-bromophenyl)etherthat was prepared using 3-bromophenol and 4-fluorobenzonitrile asstarting materials. The product was obtained as a white solid.

Example 17 4-(4-Cyanophenoxy)-2-Methylphenylboronic acid (C99)

By following the procedures described for the synthesis of C21, thetitle compound was acquired from(4-cyanophenyl)(4-bromo-3-methylphenyl)ether that was prepared using4-bromo-3-methylphenol and 4-fluorobenzonitrile as starting materials.The product was obtained as a cream solid.

Example 18 Cyclic Boronic Esters

Additional compounds can be produced by the methods described herein. Bychoosing the appropriate starting material such as 1 or 3, the methodsdescribed herein can be used to formulate the following compounds.

Exemplary compounds of structure I are provided: 18a Ethyl2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)acetate (C41); 18b2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)acetic acid (C42);18c 6-(thiophen-2-ylthio)benzo[c][1,2]oxaborol-1 (3H)-ol (C43); 18d6-(4-fluorophenylthio) benzo[c][1,2]oxaborol-1 (3H)-ol (C44); 18e1-(3-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)methyl)phenyl)pentan-1-one (C45); 18f2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-1-(piperidin-1-yl)ethanone(C46); 18g2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethanone(C47); 18h 6-(4-(pyridin-2-yl)piperazin-1-yl)benzo[c][1,2]oxaborol-1(3H)-ol (C48); 18i 6-nitrobenzo[c][1,2]oxaborol-1 (3H)-ol (C49); 18j6-aminobenzo[c][1,2]oxaborol-1 (3H)-ol (C50); 18k6-(dimethylamino)benzo[c][1,2] oxaborol-1 (3H)-ol (C51); 18lN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzamide (C52); 18m6-(4-phenylpiperazin-1-yl)benzo[c][1,2]oxaborol-1 (3H)-ol (C53); 18n6-(1H-indol-1-yl)benzo[c][1,2]oxaborol-1 (3H)-ol (C55); 18o6-morpholinobenzo[c][1,2]oxaborol-1 (3H)-ol (C56); 18p6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinonitrile(C57); 18q 5-fluoro-6-nitrobenzo[c][1,2]oxaborol-1 (3H)-ol (C58); 18r5-bromo-6-(hydroxymethyl)benzo [c][1,2]oxaborol-1 (3H)-ol (C59); 18s3,7-dihydro-1,5-dihydroxy-1H,3H-Benzo[1,2-c:4,5-c′]bis[1,2]oxaborole(C60); 18t1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-phenylurea (C61);18uN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide(C62); 18v N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)acetamide(C63); 18w 7-(hydroxymethyl)benzo[c][1,2]oxaborol-1 (3H)-ol (C64); 18x7-methylbenzo[c][1,2]oxaborol-1 (3H)-ol (C65); 18y6-(3-(phenylthio)-1H-indol-1-yl)benzo[c][1,2]oxaborol-1 (3H)-ol (C66);18z3-(1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-1H-indol-3-ylthio)propanenitrile(C67); 18aa 6-(5-methoxy-1H-indol-1-yl)benzo[c][1,2]oxaborol-1 (3H)-ol(C68); 18ab 5,6-methylenedioxybenzo[c][1,2]oxaborol-1 (3H)-ol. (C69);18ac 6-amino-5-fluorobenzo[c][1,2]oxaborol-1 (3H)-ol (C70); 18ad6-(benzylamino)-5-fluorobenzo[c][1,2]oxaborol-1 (3H)-ol (C71); 18ae6-(5-methoxy-3-(phenylthio)-1H-indol-1-yl)benzo[c][1,2]oxaborol-1(3H)-ol (C72); 18af3-(1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-5-methoxy-1H-indol-3-ylthio)propanenitrile(C73); 18ag4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-yloxy)benzonitrile(C74); 18ah 6-(5-chloro-1H-indol-1-yl)benzo[c][1,2]oxaborol-1 (3H)-ol(C75); 18ai3-(5-chloro-1-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-1H-indol-3-ylthio)propanenitrile(C76); 18aj 6-(benzylamino)benzo[c][1,2]oxaborol-1 (3H)-ol (C77); 18ak6-(dibenzylamino)benzo[c][1,2]oxaborol-1 (3H)-ol (C78); 18al7-(4-(1H-tetrazol-5-yl)phenoxy)benzo[c][1,2]oxaborol-1 (3H)-ol (C79);18am 6-(5-chloro-3-(phenylthio)-1H-indol-1-yl)benzo[c][1,2]oxaborol-1(3H)-ol (C80); 18an6-(4-(pyrimidin-2-yl)piperazin-1-yl)benzo[c][1,2]oxaborol-1 (3H)-ol(C82); 18ao 7-(benzyloxy)benzo[c][1,2]oxaborol-1 (3H)-ol (C83); 18ap4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylthio)pyridiniumchloride (C84); 18aq 6-(pyridin-2-ylthio)benzo[c][1,2]oxaborol-1 (3H)-ol(C85); 18ar 7-fluorobenzo[c][1,2]oxaborol-1 (3H)-ol (C86); 18as6-(4-(trifluoromethyl)phenoxy)benzo[c][1,2]oxaborol-1 (3H)-ol (C87);18at 6-(4-chlorophenylthio)benzo[c][1,2]oxaborol-1 (3H)-ol (C88); 18au6-(4-chlorophenylsulfinyl)benzo[c][1,2]oxaborol-1 (3H)-ol (C89); 18av6-(4-chlorophenylsulfonyl)benzo[c][1,2]oxaborol-1 (3H)-ol (C90); 18awN-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)-N-(phenylsulfonyl)benzenesulfonamide(C91); 18ax 6-(4-(trifluoromethyl)phenylthio)benzo[c][1,2]oxaborol-1(3H)-ol (C92); 18ay6-(4-(trifluoromethyl)phenylsulfinyl)benzo[c][1,2]oxaborol-1 (3H)-ol(C93); 18az 6-(4-(methylthio)phenylthio)benzo[c][1,2]oxaborol-1 (3H)-ol(C94); 18ba 6-(p-tolylthio)benzo[c][1,2]oxaborol-1 (3H)-ol (C95); 18bb3-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)methyl)benzonitrile(C96).

Example 19 19a5-(4-Cyanobenzyloxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (D1)

A mixture of 4-bromo-3-formylphenol (25.2 g, 125 mmol),tert-butyldimethylchlorosilane (21.4 g, 138 mmol), and imidazole (9.63g, 140 mmol) in dichloromethane (300 mL) was stirred at room temperaturefor 3 hours. Water was added, and the mixture was extracted withchloroform. The organic layer was washed with brine and dried onanhydrous sodium sulfate. The solvent was removed under reduced pressureto give the crude silyl ether (40.9 g, quant). To a solution of thecrude silyl ether (36.8 g, 117 mmol) in methanol (300 mL) was addedsodium borohydride (2.22 g, 58.4 mmol) portionwise at 0° C., and themixture was stirred at room temperature for 1 hour. Water was addedslowly, and the solvent was removed under reduced pressure to about athird of volume. The mixture was extracted with ethyl acetate. Theorganic layer was washed with brine and dried on anhydrous sodiumsulfate. The solvent was removed under reduced pressure to give2-bromo-5-tert-butyldimethylsiloxybenzylalcohol (36.9 g, quant).

¹H-NMR (300 MHz, CDCl₃) δ (ppm) 0.20 (s, 6H), 0.98 (s, 9H), 4.67 (br s,1H), 6.65 (dd, J=8.2, 2.6 Hz, 1H), 6.98 (d, J=2.9 Hz, 1H), 7.36 (d,J=8.8 Hz, 1H).

To a solution of 2-bromo-5-tert-butyldimethylsiloxybenzylalcohol (36.9g, 116 mmol) and diisopropylethylamine (26.0 mL, 150 mmol) indichloromethane (300 mL) was added chloromethyl methyl ether (11.0 mL,145 mmol), and the mixture was stirred at room temperature forovernight. Water was added, and the mixture was extracted withchloroform. The organic layer was washed with brine and dried onanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by silica gel columnchromatography (96:4 hexane/ethyl acetate) to give1-bromo-4-tert-butyldimethylsiloxy-2-methoxymethoxymethylbenzene (39.3g, 94%).

¹H-NMR (300 MHz, CDCl₃) δ (ppm) 0.19 (s, 6H), 0.98 (s, 9H), 3.43 (s,3H), 4.59 (s, 2H), 4.75 (s, 2H), 6.64 (dd, J=8.5, 2.9 Hz, 1H), 6.98 (d,J=2.9 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H).

To a solution of1-bromo-4-tert-butyldimethylsiloxy-2-methoxymethoxymethylbenzene (34.2g, 94.8 mmol) in tetrahydrofuran (100 mL) was added tetrabutylammoniumfluoride (1 mol/L in tetrahydrofuran, 50 mL), and the mixture wasstirred at room temperature for 1 hour. Water was added, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine and dried on anhydrous sodium sulfate. The solvent was removedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (2:1 hexane/ethyl acetate) to give4-bromo-3-(methoxymethoxymethyl)phenol (25.9 g, quant).

¹H-NMR (300 MHz, CDCl₃) δ (ppm) 3.44 (s, 3H), 4.61 (s, 2H), 4.77 (s,2H), 6.66 (dd, J=8.5, 2.9 Hz, 1H), 7.00 (d, J=2.9 Hz, 1H), 7.37 (d,J=8.5 Hz, 1H).

A mixture of 4-bromo-3-(methoxymethoxymethyl)phenol (2.47 g, 10.0 mmol),4-cyanobenzyl bromide (1.88 g, 9.50 mmol), and potassium carbonate (1.66g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 70° C. forovernight. Water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with brine and dried on anhydroussodium sulfate. The solvent was removed under reduced pressure to give4-[4-bromo-3-(methoxymethoxymethyl)phenoxymethyl] benzonitrile (1.88 g,95%).

The above compound was converted into the target compound in a similarmanner to Example 4.2.q (C17).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.90 (s, 2H), 5.25 (s, 2H), 6.98 (dd,J=7.9, 2.1 Hz, 1H), 7.03 (d, J=1.8 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.64(d, J=8.5 Hz, 2H), 7.86 (d, J=8.5 Hz, 1H), 9.01 (s, 1H).

19b 5-(3-Chloro-4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D2)

A mixture of 2-bromo-5-hydroxybenzaldehyde (60.0 g, 299 mmol), ethyleneglycol (56 mL, 1.00 mol), and p-toluenesulfonic acid (1.14 g, 5.98 mmol)in toluene (450 mL) was refluxed with Dean-Stark head for overnight.Potassium carbonate (3 g) was added, and the mixture was extracted withethyl acetate. The organic layer was washed with brine and dried onanhydrous sodium sulfate. The solvent was removed under reduced pressureto give 4-bromo-3-(1,3-dioxolan-2-yl)phenol (66.1 g, 90%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 3.9-4.1 (m, 4H), 5.81 (s, 1H), 6.71(dd, J=8.5, 2.9 Hz, 1H), 6.96 (d, J=2.9 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H),9.81 (br s, 1H).

A mixture of 2-chloro-4-fluorobenzonitrile (4.43 g, 28.4 mmol),4-bromo-3-(1,3-dioxolan-2-yl)phenol (6.96 g, 28.4 mmol), and potassiumcarbonate (4.70 g, 34.1 mmol) in N,N-dimethylformamide (60 mL) wasstirred at 100° C. under nitrogen atmosphere overnight. The mixture waspoured into ethyl acetate/water. The organic layer was washed with brineand dried on anhydrous sodium sulfate. The solvent was removed underreduced pressure to give crude4-(4-bromo-3-(1,3-dioxolan-2-yl)phenoxy)-3-chlorobenzonitrile (10.8 g),which was used for the next step without purification.

The compound obtained above (10.8 g) was dissolved in tetrahydrofuran(40 mL) and 3 M HCl (20 mL) was added, and the mixture was refluxed for2 h. Water was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine and dried on anhydrous sodiumsulfate. The solvent was removed under reduced pressure to give4-(4-bromo-3-formylphenoxy)-3-chlorobenzonitrile (9.76 g, quant.).

¹H-NMR (300 MHz, CDCl₃) δ (ppm) 6.94 (dd, J=8.5, 2.3 Hz, 1H), 7.06 (d,J=2.3 Hz, 1H), 7.21 (dd, J=8.5, 2.9 Hz, 1H), 7.59 (d, J=2.9 Hz, 1H),7.64 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 10.2 (s, 1H).

To a solution of 4-(4-bromo-3-formylphenoxy)-3-chlorobenzonitrile (9.25g, 27.4 mmol) in methanol (80 mL) was added sodium borohydride (522 mg,13.7 mmol) portionwise at 0° C., and the mixture was stirred at roomtemperature for 1 h. The solvent was removed to about a half volume, 1 MHCl was added, and the mixture was poured into ethyl acetate/water. Theorganic layer was washed with brine and dried on anhydrous sodiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by silica gel chromatography (8:2 to 7:3 hexane/ethylacetate) to give4-(4-bromo-3-(hydroxymethyl)phenoxy)-3-chlorobenzonitrile (8.19 g, 3steps, 85%).

¹H-NMR (300 MHz, CDCl₃) δ (ppm) 1.87 (br s, 1H), 4.75 (s, 2H), 6.89 (dd,J=8.5, 2.9 Hz, 1H), 6.92 (dd, J=8.8, 2.6 Hz, 1H), 7.03 (d, J=2.6 Hz,1H), 7.27 (d, J=2.9 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.8 Hz,1H).

To a solution of4-(4-bromo-3-(hydroxymethyl)phenoxy)-3-chlorobenzonitrile (4.08 g, 12mmol) in toluene (160 mL) was added triisopropyl borate (4.15 mL, 18.0mmol), and the solvent was distilled out through Dean-Stark head to avolume of ca. 3 mL. Tetrahydrofuran (3 mL) was added, and the mixturewas cooled down to −78° C. Then n-butyllithium (1.6 M in hexanes, 7.5mL, 12 mmol) was added dropwise, and the mixture was allowed to warm toroom temperature. The reaction was quenched with 1 M HCl, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine and dried on anhydrous sodium sulfate. The solvent wasremoved under reduced pressure and the residue was purified by silicagel chromatography (70:30 to 55:45 hexane/ethyl acetate) followed bytrituration with isopropyl ether to give5-(3-Chloro-4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole (1.64 g, 39%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.97 (s, 2H), 7.08 (dd, J=8.9, 2.3 Hz,1H), 7.13 (dd, J=7.9, 2.1 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 7.36 (d,J=2.3 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 9.25 (s,1H).

19c 5-(4-Cyano-3-methylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D3)

This compound was obtained in a similar manner to Example 19b (D2) from4-fluoro-2-methylbenzonitrile and 4-bromo-3-(1,3-dioxolan-2-yl)phenol.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 2.43 (s, 3H), 4.95 (s, 2H), 6.94 (dd,J=8.5, 2.6 Hz, 1H), 7.06 (dd, J=7.9, 2.3 Hz, 1H), 7.08 (d, J=2.3 Hz,1H), 7.12 (d, J=2.1 Hz, 1H), 7.77 (d, J=8.5 Hz, 2H), 9.21 (s, 1H).

19d 5-(2-Chloro-4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D4)

This compound was obtained in a similar manner to Example 19b (D2) from3-chloro-4-fluorobenzonitrile and 4-bromo-3-(1,3-dioxolan-2-yl)phenol.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.94 (s, 2H), 7.07 (d, J=8.2 Hz, 1H),7.11 (d, J=0.9 Hz, 1H), 7.12 (dd, J=8.8, 1.2 Hz, 1H), 7.7-7.9 (m, 2H),8.24 (d, J=2.1 Hz, 1H), 9.23 (s, 1H).

19e5-(4-Cyano-3-trifluoromethylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D5)

This compound was obtained in a similar manner to Example 19b (D2) from4-fluoro-2-trifluoromethylbenzonitrile and4-bromo-3-(1,3-dioxolan-2-yl)phenol.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.97 (s, 2H), 7.16 (dd, J=7.0, 2.1 Hz,1H), 7.24 (d, J=2.1 Hz, 1H), 7.35 (dd, J=8.5, 2.3 Hz, 1H), 7.60 (d,J=2.6 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 9.27 (s,1H).

19f5-(4-Cyano-3-methoxycarbonylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D6)

A mixture of methyl 2-cyano-5-fluorobenzoate (4.48 g, 25.0 mmol),2-bromo-5-hydroxybenzaldehyde (5.03 g, 25.0 mmol), and potassiumcarbonate (4.14 g, 30.0 mmol) in N,N-dimethylformamide (50 mL) wasstirred at 80° C. overnight. Water was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brineand dried on anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gelchromatography (chloroform) to give methyl5-(4-bromo-3-formylphenoxy)-2-cyanobenzoate (5.35 g, 71%).

¹H-NMR (300 MHz, CDCl₃) δ (ppm) 3.98 (s, 3H), 7.18-7.24 (m, 2H), 7.58(d, J=2.9 Hz, 1H), 7.66 (d, J=2.6 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.78(d, J=8.5 Hz, 1H), 10.3 (s, 1H).

A mixture of methyl 5-(4-bromo-3-formylphenoxy)-2-cyanobenzoate (11.9 g,33.1 mmol), bis(pinacolato)diboron (8.89 g, 35.0 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (678 mg,0.828 mmol), and potassium acetate (9.75 g, 99.0 mmol) in 1,4-dioxane(160 mL) was stirred under nitrogen atmosphere at 80° C. overnight. Themixture was filtered through a Celite pad, and the solvent was removedunder reduced pressure. Silica gel column (65:35 hexane/ethyl acetate)gave methyl2-cyano-5-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzoate(15.7 g).

To a solution of methyl2-cyano-5-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzoate(15.7 g) in methanol (150 mL) was added sodium borohydride (646 mg, 17.0mmol) portionwise at 0° C. The mixture was stirred at room temperaturefor 1 h. The mixture was acidified with 6 M HCl, and extracted withethyl acetate. The organic layer was washed with brine and dried onanhydrous sodium sulfate. The solvent was removed under reduced pressureand the residue was purified by silica gel chromatography (6:4 to 4:6hexane/ethyl acetate) followed by recrystallization from methanol/waterto give 5-(4-cyano-3-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole(6.34 g, 62%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 3.86 (s, 3H), 7.13 (dd, J=7.9, 2.1 Hz,1H), 7.20 (d, J=2.1 Hz, 1H), 7.39 (dd, J=8.6, 2.6 Hz, 1H), 7.55 (d,J=2.6 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 9.25 (s,1H).

19g5-(4-Carbamoyl-3-methoxycarbonylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D7)

A mixture of5-(4-Cyano-3-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole (5.25g, 17.0 mmol) and 1 M NaOH (50 mL) in methanol (150 mL) was stirred atroom temperature for 1 h. The mixture was acidified with 6 M HCl andextracted with ethyl acetate. The organic layer was washed with brineand dried on anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gelchromatography (ethyl acetate) followed by trituration with diisopropylether to give5-(4-Carbamoyl-3-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole(1.09 g, 19%)

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 3.70 (s, 3H), 4.94 (s, 2H), 7.0-7.1(m, 2H), 7.15-7.25 (m, 2H), 7.40 (br s, 1H), 7.61 (d, J=8.8 Hz, 1H),7.75 (d, J=7.9 Hz, 1H), 7.90 (br s, 1H), 9.19 (s, 1H).

19h 5-(3-Carboxy-4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D8)

A mixture of5-(4-Cyano-3-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole (5.25g, 17.0 mmol) and 1 M NaOH (50 mL) in methanol (150 mL) was stirred atroom temperature for 1 h. The mixture was acidified with 6 M HCl andextracted with ethyl acetate. The organic layer was washed with brineand dried on anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gelchromatography (ethyl acetate to 3:1 chloroform/methanol) followed bytrituration with ethyl acetate to give5-(3-carboxy-4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole (810 mg, 16%)

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.95 (s, 2H), 7.04-7.16 (m, 3H), 7.43(d, J=2.3 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 9.27(br s, 1H).

19i5-(1,3-Dihydro-1-hydroxy-2,1-benzoxaborol-5-yloxy)isoindoline-1,3-dione(D9)

A mixture of5-(4-Carbamoyl-3-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole(560 mg, 1.71 mmol) and 1 M NaOH (5 mL) in methanol (15 mL) was stirredat room temperature for 10 min. The mixture was acidified with 6 M HCl,and extracted with ethyl acetate. The organic layer was washed withbrine and dried on anhydrous sodium sulfate. The solvent was removedunder reduced pressure and the residue was triturated with ethyl acetateto give5-(1,3-Dihydro-1-hydroxy-2,1-benzoxaborol-5-yloxy)isoindoline-1,3-dione(380 mg, 75%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.96 (s, 2H), 7.11 (dd, J=7.9, 1.5 Hz,1H), 7.17 (s, 1H), 7.25 (d, J=2.3 Hz, 1H), 7.38 (dd, J=8.2, 2.3 Hz, 1H),7.82 (d, J=8.2 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 9.23 (s, 1H), 11.3 (brs, 1H).

19j 5-(4-Cyano-3-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D10)

This compound was obtained in a similar manner to Example 19n (D14) from4-fluoro-3-hydroxybenzonitrile and 4-bromo-3-(1,3-dioxolan-2-yl)phenol.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.96 (s, 2H), 6.49 (d, J=2.3 Hz, 1H),6.55 (dd, J=8.8, 2.3 Hz, 1H), 7.08 (dd, J=7.9, 2.1 Hz, 1H), 7.15 (d,J=1.8 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 9.23 (s,1H), 11.2 (s, 1H).

19k 5-(4-Cyano-3-acetoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D11)

A mixture of5-(4-cyano-3-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(900 mg, 3.37 mmol), acetic anhydride (1.7 mL, 18 mmol), triethylamine(1.4 mL, 10 mL) in N,N-dimethylformamide (10 mL) was stirred at roomtemperature overnight. The mixture was acidified with 1 M HCl andextracted with ethyl acetate. The organic layer was washed with brineand dried on anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gelchromatography (1:1 hexane/ethyl acetate) to give5-(4-cyano-3-acetoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(818 mg, 79%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 2.31 (s, 3H), 4.96 (s, 2H), 7.04 (dd,J=8.5, 2.6 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.12 (dd, J=7.9, 2.1 Hz,1H), 7.20 (d, J=2.0 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.91 (d, J=8.6 Hz,1H), 9.25 (s, 1H).

19l 5-(4-Cyano-3-methoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D12)

To a solution of5-(4-cyano-3-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(100 mg, 0.375 mmol) and iodomethane (0.070 mL. 1.1 mmol) inN,N-dimethylformamide (10 mL) was added sodium hydride (60% oildispersion, 45 mg, 1.1 mmol) at 0° C. under nitrogen atmosphere, and themixture was stirred at room temperature for 2 h. Water and 1 M HCl wereadded and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine and dried on anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and the residue was treatedwith hexane/diisopropyl ether to give5-(4-cyano-3-methoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (92mg, 87%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 3.86 (s, 3H), 4.96 (s, 2H), 6.56 (dd,J=8.5, 2.1 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 7.09 (dd, J=8.2, 2.1 Hz,1H), 7.14 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 9.22(s, 1H).

19m 5-(3-Chloro-2-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D13)

This compound was obtained in a similar manner to Example 19b (D2) from2-chloro-6-fluorobenzonitrile and 4-bromo-3-(1,3-dioxolan-2-yl)phenol.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.96 (s, 2H), 6.97 (d, J=8.5 Hz, 1H),7.16 (dd, J=7.9, 2.1 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.49 (d, J=8.2 Hz,1H), 7.66 (t, J=8.2 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 9.25 (s, 1H).

19n 5-(4-Cyano-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D14)

To a solution of 4-fluoro-3-hydroxybenzonitrile (25.0 g, 182 mmol),diisopropylethylamine (47.7 mL, 273 mmol) in dichloromethane (530 mL)was added chloromethyl methyl ether (16.6 mL, 219 mmol) dropwise at 0°C., and the mixture was stirred at room temperature overnight. Water wasadded, and the mixture was extracted with dichloromethane. The organiclayer was washed with brine and dried on anhydrous sodium sulfate. Thesolvent was removed under reduced pressure to give4-fluoro-3-methoxymethoxybenzonitrile (33.0 g, quant.), which was usedfor the next step without purification.

A mixture of 4-fluoro-3-methoxymethoxybenzonitrile (33.0 g, 182 mmol),4-bromo-3-(1,3-dioxolan-2-yl)phenol (44.6 g, 182 mmol), and potassiumcarbonate (30.1 g, 218 mmol) in N,N-dimethylformamide (370 mL) wasstirred at 100° C. under nitrogen atmosphere overnight. The mixture waspoured into ethyl acetate/water. The organic layer was washed with brineand dried on anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was passed silica gel short column(3:1 hexane/ethyl acetate) followed by trituration with hexane/ethylacetate to give4-(4-bromo-3-(1,3-dioxolan-2-yl)phenoxy)-3-methoxymethoxybenzonitrile(32.6 g, 44%),

¹H-NMR (300 MHz, CDCl₃) δ (ppm) 3.46 (s, 3H), 4.0-4.2 (m, 4H), 5.20 (s,2H), 6.03 (s, 1H), 6.86 (dd, J=8.5, 2.9 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H),7.24-7.30 (m, 2H), 7.54 (d, J=8.8 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H).

To a solution of4-(4-bromo-3-(1,3-dioxolan-2-yl)phenoxy)-3-methoxymethoxybenzonitrile(32.2 g, 79.3 mmol) in tetrahydrofuran (300 mL) was added 3 M HCl (100mL), and the mixture was refluxed for 2 h. Water was added, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine and dried on anhydrous sodium sulfate. The solvent wasremoved under reduced pressure to give4-(4-bromo-3-formylphenoxy)-3-hydroxybenzonitrile (25.8 g, quant.).

A mixture of 4-(4-bromo-3-formylphenoxy)-3-hydroxybenzonitrile (20.5 g,64.5 mmol), bis(pinacolato)diboron (17.2 g, 67.7 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.32 g,1.61 mmol), and potassium acetate (19.1 g, 194 mmol) in 1,4-dioxane (260mL) was stirred under nitrogen atmosphere at 80° C. overnight. Themixture was filtered through a Celite pad, and the solvent was removedunder reduced pressure. Silica gel column (ethyl acetate) gave methyl4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3-hydroxybenzonitrile(25.1 g).

To a solution of methyl4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3-hydroxybenzonitrile(25.1 g) in methanol (300 mL) was added sodium borohydride (2.45 g, 64.5mmol) portionwise at 0° C. The mixture was stirred at room temperaturefor 1 h. The solvent was removed under reduced pressure to about a thirdof volume. The mixture was acidified with 6 M HCl, and extracted withethyl acetate. The organic layer was washed with brine and dried onanhydrous sodium sulfate. The solvent was removed under reduced pressureand the residue was purified by silica gel chromatography (7:3 to 6:4hexane/acetone) followed by recrystallization from acetone/water andtrituration with ethyl acetate to give5-(4-cyano-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(10.9 g, 63%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.90 (s, 2H), 6.90-6.95 (m, 2H), 7.09(d, J=7.9 Hz, 1H), 7.26-7.33 (m, 2H), 7.69 (d, J=7.9 Hz, 1H), 9.12 (s,1H), 10.4 (br s, 1H).

19o 5-(4-Cyano-2-methoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D15)

This compound was obtained in a similar manner to Example 271 (D12) from5-(4-cyano-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D14) and iodomethane.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 3.80 (s, 3H), 4.90 (s, 2H), 6.90-6.96(m, 2H), 7.12 (d, J=8.2 Hz, 1H), 7.44 (dd, J=8.2, 2.1 Hz, 1H), 7.67 (d,J=1.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 9.13 (s, 1H).

19p5-[4-Cyano-2-(ethoxycarbonylmethoxy)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D16)

This compound was obtained in a similar manner to Example 191 (D12) from5-(4-cyano-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D14) and ethyl bromoacetate.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 1.17 (t, J=7.0 Hz, 3H), 4.12 (q, J=7.0Hz, 2H), 4.91 (s, 4H), 6.94-6.99 (m, 2H), 7.13 (d, J=8.5 Hz, 1H), 7.47(dd, J=8.5, 1.8 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H),9.14 (s, 1H).

19q5-[2-(Carboxymethoxy)-4-cyanophenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D17)

A mixture of5-[4-Cyano-2-(ethoxycarbonylmethoxy)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D16) (216 mg, 0.612 mmol) and 1 M NaOH (2 mL in methanol (8 mL) wasstirred at room temperature for 1 h. The mixture was acidified with 1 MHCl and extracted with ethyl acetate. The organic layer was washed withbrine and dried on anhydrous sodium sulfate. The solvent was removedunder reduced pressure and the residue was treated with hexane to give5-[2-(Carboxymethoxy)-4-cyanophenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(82 mg, 41%)

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.82 (s, 2H), 4.90 (s, 2H), 6.94-7.00(m, 2H), 7.11 (d, J=8.2 Hz, 1H), 7.45 (dd, J=8.5, 1.8 Hz, 1H), 7.62 (s,1H), 7.70 (d, J=8.5 Hz, 1H), 9.14 (s, 1H), 13.1 (brs, 1H).

19r5-(4-Carboxy-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D18)

A mixture of5-(4-cyano-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D14) (4.00 g, 15.0 mmol) and 6 M NaOH (30 mL) in methanol (60 mL) and1,4-dioxane (60 mL) was refluxed for 5 days. The mixture was cooled onan ice bath and acidified with 6 M HCl, then extracted with ethylacetate. The organic layer was washed with brine and dried on anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was recrystallized from ethyl acetate to give5-(4-carboxy-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(1.29 g, 30%). Silica gel column (3:7 to 2:8 hexane/ethyl acetate) ofthe filtrate followed by trituration with ethyl acetate gave another1.00 g (23%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.89 (s, 2H), 6.85 (d, J=1.5 Hz, 1H),6.90 (dd, J=7.9, 2.1 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 7.41 (dd, J=8.2,2.1 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 9.08 (s,1H), 9.98 (s, 1H), 12.8 (br s, 1H).

19s5-(4-Ethoxycarbonyl-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D19)

A mixture of5-(4-carboxy-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(1.95 g, 6.82 mmol) and sulfuric acid (1.5 mL) in ethanol (75 mL) wasrefluxed for 6 h. Water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with brine and dried onanhydrous sodium sulfate. The solvent was removed under reducedpressure. Silica gel column (6:4 to 5:5 hexane/acetone) followed byrecrystallization from diisopropyl ether gave5-(4-Ethoxycarbonyl-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(1.65 g, 77%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 1.29 (t, J=7.0 Hz, 3H), 4.27 (q, J=7.0Hz, 1H), 4.89 (s, 2H), 6.86 (s, 1H), 6.91 (d, J=8.2 Hz, 1H), 7.05 (d,J=8.2 Hz, 1H), 7.43 (dd, J=8.5, 2.1 Hz, 1H), 7.56 (s, 1H), 7.67 (d,J=8.2 Hz, 1H), 9.09 (s, 1H), 10.1 (s, 1H).

19t5-(4-Ethoxycarbonyl-2-methoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D20)

This compound was obtained in a similar manner to Example 191 (D12) from5-(4-ethoxycarbonyl-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D19) and iodomethane.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 1.31 (t, J=7.0 Hz, 3H), 3.80 (s, 3H),4.31 (q, J=7.0 Hz, 2H), 4.89 (s, 3H), 6.86-6.94 (m, 2H), 7.11 (d, J=8.5Hz, 1H), 7.59 (dd, J=8.2, 1.8 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.68 (d,J=7.9 Hz, 1H), 9.11 (s, 1H).

19u5-[4-Ethoxycarbonyl-2-(cyclopentyloxy)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D21)

This compound was obtained in a similar manner to Example 191 (D12) from5-(4-ethoxycarbonyl-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D19) and cyclopentyl iodide.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 1.2-1.6 (m, 6H), 1.30 (t, J=7.0 Hz,3H), 1.7-1.9 (m, 2H), 4.30 (q, J=7.0 Hz, 2H), 4.87 (s, 2H), 4.87 (m,1H), 6.84 (s, 1H), 6.88 (d, J=7.9 Hz, 1H), 7.17 (d, J=7.9 Hz, 1H),7.55-7.61 (m, 2H), 7.65 (d, J=7.9 Hz, 1H), 9.09 (s, 1H).

19v5-[4-Ethoxycarbonyl-2-(4-cyanopyridin-2-yloxy)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D22)

A mixture of5-(4-ethoxycarbonyl-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D19) (200 mg, 0.637 mmol), 2-chloro-5-pyridin-5-carbonitrile (106 mg,0.764 mmol), and potassium carbonate (264 mg, 1.90 mmol) inN,N-dimethylformamide (4 mL) was stirred at 70° C. under nitrogenatmosphere for 2 h. The mixture was poured into ethyl acetate/dilutedHCl. The organic layer was washed with brine and dried on anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified by silica gel column (6:4 hexane/acetone) andpreparative TLC (5:5 hexane/acetone) to give5-[4-Ethoxycarbonyl-2-(4-cyanopyridin-2-yloxy)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(133 mg, 50%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 1.29 (t, J=7.0 Hz, 1H), 4.29 (q, J=7.0Hz, 2H), 4.88 (s, 2H), 6.91 (dd, J=8.2, 2.3 Hz, 1H), 6.95 (d, J=2.1 Hz,1H), 7.13 (d, J=8.8 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 7.67 (d, J=7.9 Hz,1H), 7.84-7.90 (m, 2H), 8.28 (dd, J=8.8, 2.3 Hz, 1H), 8.62 (d, J=2.3 Hz,1H), 9.16 (s, 1H).

19w 5-(4-Cyano-2-formylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D23)

To a solution of 4-bromo-3-formylphenol (20.1 g, 100 mmol) in methanol(200 mL) was added sodium borohydride (1.90 g, 50.0 mmol) portionwise at0° C., and the mixture was stirred at room temperature for 1 h. Thesolvent was removed under reduced pressure to a half volume, 6 M HCl (50mL) was added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine and dried on anhydrous sodiumsulfate. The solvent was removed under reduced pressure to give4-bromo-3-hydroxymethylphenol (19.4 g, 96%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.39 (d, J=5.9 Hz, 2H), 5.35 (t, J=5.9Hz, 1H), 6.56 (dd, J=8.5, 2.9 Hz, 1H), 6.97 (d, J=2.9 Hz, 1H), 7.28 (d,J=8.5 Hz, 1H), 9.61 (s, 1H).

A mixture of 4-fluoro-3-formylbenzonitrile (14.2 g, 96.0 mmol),4-bromo-3-hydroxymethylphenol (19.4 g, 96 mmol), and potassium carbonate(15.2 g, 110 mmol) in N,N-dimethylformamide (200 mL) was stirred at 70°C. under nitrogen atmosphere for 2 h. The mixture was poured into ethylacetate/water. The organic layer was washed with water twice and withbrine, then dried on anhydrous sodium sulfate. The solvent was removedunder reduced pressure, and the residue was purified by silica gelcolumn (3:1 to 7:3 hexane/ethyl acetate) to give4-[4-bromo-3-(hydroxymethyl)phenoxy]-3-formylbenzonitrile (26.0 g, 82%).

A mixture of 4-[4-bromo-3-(hydroxymethyl)phenoxy]-3-formylbenzonitrile(25.5 g, 76.8 mmol), 3,4-dihydro-2H-pyran (10.4 mL, 115 mmol), anddl-10-camphorsulfonic acid (356 mg, 2 mol %) in dichloromethane (300 mL)was stirred at room temperature for 2 h. Sodium carbonate (3 g) wasadded, and the mixture was poured into water/chloroform. The organiclayer was washed with brine and dried on anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, and the residue was purifiedby silica gel column (85:15 hexane/ethyl acetate) to give4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-formylbenzonitrile(28.0 g, 88%).

A mixture of4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-formylbenzonitrile(28.0 g, 67.3 mmol), bis(pinacolato)diboron (18.8 g, 74.0 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.37 g, 2.5mol %), and potassium acetate (19.8 g, 202 mmol) in 1,4-dioxane (270 mL)was stirred under nitrogen atmosphere at 80° C. overnight. The mixturewas filtered through a Celite pad, and the solvent was removed underreduced pressure. The residue was dissolved in tetrahydrofuran (250 mL)and was added 6 M HCl (30 mL), and the mixture was stirred at roomtemperature for 2 h. The mixture was poured into ethyl acetate/water.The organic layer was washed with brine and dried on anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and the residuewas purified by silica gel column (5:5 to 3:7 hexane/ethyl acetate)followed by recrystallization from ethyl acetate/hexane to give5-(4-cyano-2-formylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(6.61 g, 35%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.98 (s, 2H), 7.03 (d, J=8.5 Hz, 1H),7.21 (d, J=8.2 Hz, 1H), 7.27 (s, 1H), 7.82 (d, J=7.9 Hz, 1H), 8.04 (dd,J=8.8, 2.3 Hz, 1H), 8.24 (d, J=2.3 Hz, 1H), 9.27 (s, 1H), 10.4 (s, 1H).

19x5-[4-Cyano-2-(hydroxymethyl)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D24)

To a solution of5-(4-cyano-2-formylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(3.00 g, 10.8 mmol) in methanol (100 mL) was added sodium borohydride(400 mg, 10.8 mmol) portionwise at 0° C., and the mixture was stirred atroom temperature for 1 h. The solvent was removed under reduced pressureto a half volume, 1 M HCl (50 mL) was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brineand dried on anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was treated with ethyl acetate/hexaneto give5-[4-cyano-2-(hydroxymethyl)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(1.83 g, 60%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.58 (d, J=5.6 Hz, 2H), 4.93 (s, 2H),5.44 (t, J=5.6 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 7.03 (dd, J=8.2, 1.2 Hz,1H), 7.05 (s, 1H), 7.71 (dd, J=8.5, 2.3 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H),7.88 (d, J=1.2 Hz, 1H), 9.20 (s, 1H).

19y5-[4-Cyano-2-(formylaminomethyl)phenoxy]-1,3-dihydro-J-hydroxy-2,1-benzoxaborole(D25)

To a solution of4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-formylbenzonitrileobtained in Example 19w (D23) (14.6 g, 34.9 mmol) in methanol (100 mL)was added sodium borohydride (664 mg g, 17.5 mmol) portionwise at 0° C.,and the mixture was stirred at room temperature for 1 h. The solvent wasremoved under reduced pressure to a half volume, and the mixture waspoured into ethyl acetate/water. The organic layer was washed with brineand dried on anhydrous sodium sulfate. The solvent was removed underreduced pressure to give4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-(hydroxymethyl)benzonitrile(14.6 g, 100%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 1.3-1.8 (m, 6H), 3.47 (m, 1H), 3.72(m, 1H), 4.4-4.8 (m, 4H), 5.44 (t, J=5.9 Hz, 1H), 6.92 (d, J=8.5 Hz,1H), 6.96 (dd, J=8.5, 2.9 Hz, 1H), 7.17 (d, J=2.9 Hz, 1H), 7.65 (d,J=8.5 Hz, 1H), 7.71 (dd, J=8.5, 1.8 Hz, 1H), 7.87 (d, J=1.2 Hz, 1H).

To a solution of4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-(hydroxymethyl)benzonitrile(12.1 g, 28.9 mmol) in dichloromethane (100 mL) were added triethylamine(8.0 mL, 58 mmol) and methanesulfonyl chloride (2.5 mL, 32 mmol) at 0°C., and the mixture was stirred at room temperature for 1 h. The mixturewas washed with water and brine, and dried on anhydrous sodium sulfate.The solvent was removed under reduced pressure. To a solution of theresidue in N,N-dimethylformamide (100 mL) was added sodium diformylimide(3.29 g, 34.7 mmol), and the mixture was stirred at 50° C. for 2 h. Themixture was poured into ethyl acetate/water. The organic layer waswashed with brine and dried on anhydrous sodium sulfate. The solvent wasremoved under reduced pressure. To a solution of the residue in1,4-dioxane (80 mL) was added 3 M NaOH (10 mL), and the mixture wasstirred at room temperature for 1 h. The mixture was poured into ethylacetate/water. The organic layer was washed with brine and dried onanhydrous sodium sulfate. The solvent was removed under reducedpressure. The residue was purified by silica gel column (5:5 to 4:6hexane/ethyl acetate) to give4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-(formylaminomethyl)benzonitrile(8.77 g, 68%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 1.4-1.8 (m, 6H), 3.46 (m, 1H), 3.73(m, 1H), 4.37 (d, J=5.9 Hz, 2H), 4.47 (d, J=13.8 Hz, 1H), 4.67 (d,J=13.8 Hz, 1H), 4.72 (br s, 1H), 6.92 (d, J=8.5 Hz, 1H), 7.00 (d, J=8.5Hz, 1H), 7.21 (s, 1H), 7.67 (dd, J=8.8, 1.8 Hz, 1H), 7.72 (d, J=8.5 Hz,1H), 7.76 (s, 1H), 8.14 (s, 1H), 8.53 (br t, 1H).

A mixture of4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-(formylaminomethyl)benzonitrile(1.44 g, 3.24 mmol), bis(pinacolato)diboron (905 mg, 3.56 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (87 mg, 3mol %), and potassium acetate (1.01 g, 10.3 mmol) in 1,4-dioxane (25 mL)was stirred under nitrogen atmosphere at 80° C. overnight. The mixturewas filtered through a Celite pad, and the solvent was removed underreduced pressure. The residue was passed short silica gel column (4:6hexane/ethyl acetate). The crude product was dissolved intetrahydrofuran (20 mL) and was added 6 M HCl (2 mL), and the mixturewas stirred at room temperature overnight. The mixture was poured intoethyl acetate/water. The organic layer was washed with brine and driedon anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by silica gel column (4:6hexane/ethyl acetate to ethyl acetate to 2:1 ethyl acetate/methanol)followed by trituration with water to give5-[4-cyano-2-(formylaminomethyl)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(685 mg, 68%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.40 (d, J=5.9 Hz, 1H), 4.95 (s, 1H),6.92 (d, J=8.5 Hz, 1H), 7.07 (dd, J=7.9, 1.8 Hz, 1H), 7.11 (s, 1H), 7.72(dd, J=8.5, 2.1 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 8.15 (s, 1H), 8.53 (brt, 1H), 9.21 (s, 1H).

19z5-(2-Aminomethyl-4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborolehydrochloride (D26)

To a solution of5-[4-cyano-2-(formylaminomethyl)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(250 mg, 0.812 mmol) in ethanol (16 mL) was added 6 M HCl (4 mL), andthe mixture was refluxed for 2 h. The solvent was removed under reducedpressure, and the residue was treated with ether to give5-(2-aminomethyl-4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborolehydrochloride (247 mg, 98%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.14 (br s, 2H), 4.97 (s, 2H), 6.88(d, J=8.8 Hz, 1H), 7.16 (dd, J=7.9, 2.1 Hz, 1H), 7.21 (s, 1H), 7.78-7.86(m, 2H), 8.08 (d, J=1.8 Hz, 1H), 8.54 (br s, 3H), 9.29 (s, 1H).

19aa Ethyl2-ethoxy-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate(D27)

Esterification of 2,6-dichloronicotinic acid (25.5 g, 0.1328 mmol) inEtOH (200 proof, 200 mL) catalyzed with 96% H₂SO₄ (1.7 g) at refluxingtemperature for 40 h under N₂ gave the desired ethyl2,6-dichloronicotinate as grey solid (24.89 g, 0.1131 mmol, yield 85.2%)after a normal work-up.

¹H NMR (300 MHz, DMSO-d₆): δ 8.30 (d, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz,1H), 4.33 (q, J=7.2 Hz, 2H) and 1.30 (t, J=7.2 Hz, 3H) ppm.

Substitution of NaOEt (5.8 g, 1.5 eq) with ethyl 2,6-dichloronicotinate(12.5 g, 56.8 mmol) in CH₂Cl₂ was performed (Reference:US2005/0288299A1) by slow addition of the base solid to the bis-chloroester solution at 0° C. and stirred for 3 h with the cooling, thenovernight from 0° C. to r.t. More CH₂Cl₂ and water were added,separated, dried and evaporated giving a liquid (11.62 g) thatcrystallized slowly overnight. The solid was recrystallized fromdry-ice-cooling pentane affording the desired ethyl6-chloro-2-ethoxynicotinate as white crystals (9.45 g, 41.15 mmol, yield72.4%).

M.p. 33-35° C. ¹H NMR (300 MHz, DMSO-d₆): δ 8.13 (d, J=8.1 Hz, 1H), 8.16(d, J=8.1 Hz, 1H), 4.34 (q, J=7.2 Hz, 2H), 4.24 (q, J=7.2 Hz, 2H), 1.31(t, J=7.2 Hz, 3H) and 1.27 (t, J=7.2 Hz, 3H) ppm.

Coupling reaction of ethyl 6-chloro-2-ethoxynicotinate (9.45 g, 41.15mmol) with 2-bromo-5-hydroxybenzaldehyde (8.27 g, 41.15 mmol) in thepresence of K₂CO₃ (8.53 g, 1.5 eq) in DMF (100 mL) for 2 h at 100° C.and overnight at 80° C. under N₂ provided a crude residue afterfiltration and evaporation. The residue was purified by silica gelcolumn chromatography (hexane:EtOAc=7:1, v/v) and recrystallization fromhexane and pentane affording the desired ethyl6-(4-bromo-3-formylphenoxy)-2-ethoxynicotinate as white solid (8.35 g,21.15 mmol, yield 51.4%).

¹H NMR (300 MHz, DMSO-d₆): δ 10.17 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 7.85(d, J=8.4 Hz, 1H), 7.67 (d, J=3.3 Hz, 1H), 7.54 (dd, J=8.4 & 2.8 Hz,1H), 6.68 (d, J=8.4 Hz, 1H), 4.21 (q, J=7.5 Hz, 2H), 4.05 (q, J=7.2 Hz,2H), 1.26 (t, J=7.2 Hz, 3H) and 1.14 (t, J=7.1 Hz, 3H) ppm.

Catalytic boronylation of ethyl6-(4-bromo-3-formylphenoxy)-2-ethoxynicotinate (8.35 g, 21.15 mmol) withbis-pinacol-diboron (6.5 g, 25.38 mmol), KOAc (6.2 g, 63.45 mmol) andPd(OAc)₂ (0.25 g) in DMF (100 mL) at 80° C. for 30 min under N₂generated a single component as monitored by TLC, but another compoundwas showed up after overnight standing of the reaction mixture at r.t.Normal work-up gave a crude oil (13.5 g) containing the desired ethyl2-ethoxy-6-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinate,which was used for the next reaction.

Reduction of the crude oil (13.5 g) containing ethyl2-ethoxy-6-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinatewith NaBH₄ (2.3 g) in EtOH (200 proof, 250 mL) at 0° C. for 30 min wascompleted as monitored by TLC. HCl (6N) was added and then evaporated,dissolved in EtOAc, washed with water and purified by silica gel columnchromatography (hexane:EtOAc=2:1). ¹H NMR indicated the oil obtained wasactually the uncyclized ethyl2-ethoxy-6-(3-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinate.

Cyclization of ethyl2-ethoxy-6-(3-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenoxy)nicotinateobtained above was quickly performed in EtOH and 6N HCl and subsequentevaporation. Water was added to the residue and then acetone was slowlyadded with sonication to get the crystals that were filtered and washedwith water and hexane. The solid was dried under high vacuum overnightgiving the desired title compound ethyl2-ethoxy-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate(2.287 g, 6.66 mmol).

¹H NMR (300 MHz, DMSO-d₆): δ 9.22 (s, 1H), 8.18 (d, J=8.1 Hz, 1H), 7.76(d, J=7.8 Hz, 1H), 7.24 (s, 1H), 7.16 (dd, J=7.8 & 1.8 Hz, 1H), 6.57 (d,J=8.1 Hz, 1H), 4.97 (s, 2H), 4.21 (q, J=7.5 Hz, 2H), 4.09 (q, J=7.2 Hz,2H), 1.25 (t, J=7.2 Hz, 3H) and 1.16 (t, J=7.2 Hz, 3H) ppm. Purity(HPLC): 100% at both 220 nm and 254 nm. MS: m/z=342 (M−1, ESI−).

19ab2-(5-cyano-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)phenoxy)-N,N-diethylacetamide(D28)

A mixture of5-[2-(Carboxymethoxy)-4-cyanophenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D17) (1.00 g, 3.08 mmol), EDCI (1.77 g, 9.24 mmol), HOBT (1.25 g, 9.24mmol), diethylamine (0.96 mL, 9.24 mmol), and 4-dimethylaminopyridine(75 mg, 0.62 mmol) in DMF (20 mL) was stirred at room temperatureovernight. Water was added, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified with silica gel chromatography (9:1chloroform/methanol). The combined fractions were put under reducedpressure to remove solvent and then washed with water and toluene. Thesolvent was again removed under reduced pressure. Another silica gelchromatography column was used (5:5 acetone:hexane). The desiredfractions were combined and the solvent was removed under reducedpressure. The residue was recrystallized using hexanes anddiisopropylether. Pure2-(5-cyano-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)phenoxy)-N,N-diethylacetamide(0.662 g, 57%) was obtained.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 1.00 (t, J=6.75 Hz, 3H), 1.09 (t,J=7.03, 3H), 3.2-3.3 (m, 4H), 4.9 (d, J=9.01 Hz, 1H), 6.9-7.0 (m, 2H),71.-7.2 (dd, J=8.36, 1.03 Hz, 1H), 7.42 (m, 1H), 7.54 (s, 1H), 7.69 (m,1H), 9.12 (d, J=1.17 Hz, 1H).

19ac4-(2-(5-cyano-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)phenoxy)acetyl)-1-methylpiperazinehydrochloride (D29)

This compound was prepared in the similar manner to that of (D28).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 2.73 (s, 3H), 2.9-3.1 (m, 4H), 3.3-3.5(m, 2H), 3.8-3.9 (m, 1H), 4.3-4.4 (m, 1H), 4.90 (s, 2H), 5.02 (d, J=8.2Hz, 2H), 6.96 (m, 2H), 7.14 (d, J=8.2 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H),7.62 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 9.15 (s, 1H), 10.91 (s, 1H).

19ad5-[4-Cyano-2-(tert-butoxycarbonylmethoxy)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D30)

This compound was obtained in a similar manner to Example 191 (D12) from5-(4-cyano-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D14) and tertiary butyl bromoacetate.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 1.38 (s, 9H), 4.79 (s, 2H), 4.90 (s,2H), 6.96 (m, 2H), 7.14 (d, J=8.5 Hz, 1H), 7.46 (dd, J=1.8, 8.5 Hz, 1H),7.59 (d, J=1.0 Hz, 1H), 7.65 (m, 1H), 9.13 (s, 1H).

19ae2-((5-cyano-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)phenoxy)methyl)pyridinehydrochloride (D31)

This compound was obtained in a similar manner to Example 191 (D12) from5-(4-cyano-2-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D14) and 2-chloromethylpyridine hydrochloride.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 4.89 (s, 2H), 5.32 (s, 2H), 6.70 (m,2H), 7.20 (d, J=8.2 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.4-7.6 (m, 2H),7.70 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 7.88 (t, J=7.9 Hz, 1H), 8.60 (d,J=5.0, 1H).

19af4-(5-cyano-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzyl)morpholinehydrochloride (D32)

A mixture of5-(4-Cyano-2-formylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D23) (0.400 g, 1.43 mmol), morpholine (0.375 mL, 4.29 mmol), and aceticacid (0.246 mL, 4.29 mmol) in methanol (10 mL) was stirred for fiveminutes under nitrogen at room temperature. Cyanoborohydride (0.270 g,4.29 mmol) was added, and the mixture was stirred at room temperatureunder nitrogen for two hours. Water was added and the mixture wasextracted with ethyl acetate. The organic layer was washed with brineand dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure and the residue was purified by silica gelchromatography (5:5 ethyl acetate:hexanes to 4:1dichloromethane/methanol). The desired fractions were combined and thesolvent was removed under reduced pressure. Water and toluene were addedand removed under reduced pressure to give pure4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-3-(morpholinomethyl)benzonitrile(0.399 g, 80%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 2.35 (m, 4H), 3.53 (m, 6H), 4.93 (s,2H), 7.00 (m, 3H), 7.73 (dd, J=8.07, 2.50 Hz, 2H), 7.90 (d, 2.35 Hz,1H), 9.18 (s, 1H).

A mixture of4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-3-(morpholinomethyl)benzonitrile(0.391 g, 1.12 mmol), 4 M HCl in dioxane (0.335 mL, 1.34 mmol), ether(10 mL), and THF (3 mL) were stirred at room temperature for fiveminutes. Filtered the precipitate and dried under reduced pressure. Thesolid was washed in THF and the solid was again filtered and dried underreduced pressure to give the target compound (0.258 g, 60%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 3.2-3.3 (m, 3H), 3.7-4.0 (m, 5H), 4.47(s, 2H), 4.98 (s, 2H), 6.90 (d, J=8.8 Hz, 1H), 7.20 (d, J=7.9 Hz, 1H),7.27 (s, 1H), 7.8-7.9 (m, 2H), 8.28 (s, 1H), 9.29 (br s, 1H), 11.09 (brs, 1H).

19ag1-(5-cyano-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzyl)-4-methylpiperazine-1,4-diium(D33)

This compound was obtained in a similar manner to Example 19af (D32)from 5-(4-Cyano-2-formylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D23) and 1-methylpiperazine.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 2.77 (s, 3H), 3.0-4.2 (m, 10H), 4.96(s, 2H), 6.92 (d, J=8.8 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.20 (s, 1H),7.83 (m, 2H), 8.15 (s, 1H), 9.2 (br s, 1H), 11.1 (br s, 1H),

19ah1-(5-cyano-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)phenyl)-N,N-dimethylmethanaminium(D34)

This compound was obtained in a similar manner to Example 19af (D32)from 5-(4-cyano-2-formylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D23) and dimethylamine.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 2.77 (s, 6H), 4.41 (s, 2H), 4.97 (s,2H), 6.90 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.05, 1.86 Hz, 1H), 7.26 (s,1H), 7.84 (d, J=8.2, 1H), 7.88 (d, J=2.4, 1H), 8.25 (d, J=2.1, 1H), 9.32(br s, 1H).

19ai Synthesis of4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-methoxy-benzoicacid ethyl ester (D35)

4-Bromo-3-[1,3]dioxolan-2-yl-phenol (2)

To a solution of 2-bromo-5-hydroxy-benzaldehyde compound 1 (15.0 g,74.62 mmol) in toluene (100 mL) was added ethylene glycol (12.5 mL,223.86 mmol) and p-TSA (1.42 g, 7.46 mmol). The solvent was removedunder reduced pressure to give crude product 2 (20.0 g crude), which wasused in the next step without further purification. ¹H NMR 400 MHz(CDCl₃) δ: 7.38 (d, J=8.6 Hz, 1H), 7.01 (d, J=2.7 Hz, 1H), 6.62 (d,J=8.2, 2.3 Hz, 1H), 6.01 (s, 1H), 4.20-4.01 (m, 4H).

4-Fluoro-2-hydroxy-benzoic acid ethyl ester (4)

To a solution of 4-fluoro-2-hydroxybenzoic acid compound 3 (20.0 g,128.11 mmol) in ethanol (100 mL) was added conc. sulfuric acid (10 mL).The resulting mixture was heated in a 120° C. oil bath O/N. The solventwas removed under reduced pressure to give crude product, which waspurified by column chromatography (silica gel, 10% EtOAc in hexane) toafford the title compound 4 (19.9 g, 85%) as a colorless solid. ¹H NMR400 MHz (CDCl₃) δ: 11.15 (s, 1H), 7.83 (d, J=6.6 Hz, 1H), 7.81 (d, J=6.6Hz, 1H), 6.62 (dd, J=10.1, 2.3 Hz, 1H), 6.61 (dd, J=7.0, 2.0 Hz, 1H),4.41 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H); MS (ES) m/z: 185 (M+1)⁺.

4-Fluoro-2-methoxy-benzoic acid ethyl ester (5)

To a solution of compound 4 (19.9 g, 0.109 mol) in acetonitrile (200 mL)was added cesium carbonate (42.0 g, 0.129 mol). The resulting mixturewas stirred at rt for 30 min. followed by addition of methyl iodide(13.5 mL, 0.218 mol). The resulting mixture was stirred at rt O/N andfiltered through Celite®. The solvent was removed under reduced pressureto give crude product 5 (20.0 g, 93%) and used in the next step withoutfurther purification. ¹H NMR 400 MHz (CDCl₃) δ: 7.81-7.78 (m, 1H),6.60-6.58 (m, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.82 (s, 3H), 1.39 (t, J=7.0Hz, 3H); MS (ES) m/z: 199 (M+1)⁺.

4-(4-Bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-methoxy-benzoic acid ethylester (6)

To a solution of compound 2 (9.27 g, 37.83 mmol) in DMSO (50 mL) wasadded potassium carbonate (15.68 g, 113.48 mmol). The resulting mixturewas stirred at rt for 30 min. followed by addition of compound 5 (8.99g, 45.39 mmol). The resulting mixture was heated at 120° C. O/N. Thereaction mixture was diluted with EtOAc (100 mL) and washed with water(50 mL). The organic layer was dried over Na₂SO₄, and concentrated underreduced pressure to give crude product, which was purified by columnchromatography (silica gel, 10% EtOAc in hexane) to afford the titlecompound 6 (5.6 g, 35%) as a pale yellow solid. ¹H NMR 400 MHz (CDCl₃)δ: 7.81 (d, J=9.0 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.35 (s, 1H), 6.97(dd, J=8.6, 2.7 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 6.49 (dd, J=8.6, 2.4Hz, 1H), 6.01 (s, 1H), 4.39 (q, J=7.4 Hz, 2H), 4.20-4.01 (m, 4H), 3.81(s, 3H), 1.40 (t, J=7.4 Hz, 3H); MS (ES) m/z: 423 (M+1)⁺, 425 (M+3)⁺.

4-(4-Bromo-3-formyl-phenoxy)-2-methoxy-benzoic acid ethyl ester (7)

To a solution of compound 6 (5.6 g, 13.23 mmol) in THF (50 mL) at 0° C.was added 2N HCl (50 mL). The resulting mixture was stirred at rt O/N.The reaction mixture was diluted with EtOAc (100 mL) and washed withwater (50 mL). The organic layer was dried over Na₂SO₄, and concentratedunder reduced pressure to give crude product, which was purified bycolumn chromatography (silica gel, 10% EtOAc in hexane) to afford thetitle compound 7 (3.0 g, 60%) as a pale yellow solid.

¹H NMR 400 MHz (CDCl₃) δ: 10.35 (s, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.60(d, J=8.6 Hz, 1H), 7.58 (d, J=2.7 Hz, 1H), 7.19 (dd, J=8.6, 3.1 Hz, 1H),6.60 (d, J=2.0 Hz, 1H), 6.51 (dd, J=8.6, 2.3 Hz, 1H), 4.39 (q, J=7.0 Hz,2H), 3.81 (s, 3H), 1.40 (t, J=7.0 Hz, 3H); MS (ES) m/z: 379 (M+1)⁺, 381(M+3)⁺.

4-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methoxy-benzoicacid ethyl ester (8)

To a solution of compound 7 (3.0 g, 7.91 mmol) in 1,4-dioxane (20 mL)was added bis(pinacolato)diboron (2.41 g, 9.49 mmol), potassium acetate(2.33 g, 23.73 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride (0.3 g, 0.40mmol). Nitrogen gas was passed through the mixture for 10 min. and thesuspension was heated at 80° C. for 1 h. The mixture was passed throughCelite® and concentrated under reduced pressure to give crude product,which was purified by column chromatography (silica gel, 10% EtOAc inhexane) to afford the title compound 8 (3.22 g, 96%) as a colorless oil.¹H NMR 400 MHz (CDCl₃) δ: 10.61 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.81(d, J=8.6 Hz, 1H), 7.60 (d, J=2.3 Hz, 1H), 7.35 (d, J=5.5 Hz, 2H), 6.62(d, J=2.0 Hz, 1H), 6.58 (d, J=8.6 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 3.81(s, 3H), 1.42 (s, 12H), 1.20 (t, J=7.0 Hz, 3H).

4-[3-Hydroxymethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methoxy-benzoicacid ethyl ester (9)

To a solution of compound 8 (3.22 g, 7.55 mmol) in methanol (40 mL) wasadded sodium borohydride (0.373 g, 9.82 mmol) at 0° C. The resultingmixture was stirred at rt for 30 min. The solvent was removed underreduced pressure, diluted with water (50 mL) and extracted with EtOAc(2×50 mL). The combined organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure to give crude product and used inthe next step without further purification. ¹H NMR 400 MHz (CDCl₃) δ:7.91 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.01 (s, 1H), 6.98 (d,J=8.2 Hz, 1H), 6.60 (s, 1H), 6.67 (d, J=8.6 Hz, 1H), 4.65 (s, 2H), 4.39(q, J=7.0 Hz, 2H), 3.81 (s, 3H), 1.42 (s, 12H), 1.20 (t, J=7.0 Hz, 3H).

19ai4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-methoxy-benzoicacid ethyl ester (D35)

To a solution of compound 9 (2.0 g, 4.67 mmol) in methanol (50 mL) wasadded 6N HCl (10 mL) and phenylboronic acid (2.85 g, 23.36 mmol). Theresulting mixture was stirred at rt O/N. The solvent was removed underreduced pressure to give crude product, which was purified by reversephase prep HPLC using CH₃CN/H₂O (with 0.1% acetic acid) as the eluent toafford the title compound (D35) (0.66 g, 39%) as a white solid afterlyophilization. Mp 64.9-65.2° C. ¹H NMR 400 MHz (DMSO-d₆) δ: 9.20 (s,1H), 7.80 (d, J=8.2 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.18 (s, 1H), 7.16(dd, J=8.2, 2.0 Hz, 1H), 6.80 (s, 1H), 6.60 (dd, J=8.6, 2.3 Hz, 1H),4.98 (s, 2H), 4.21 (q, J=7.0 Hz, 2H), 3.81 (s, 3H), 1.20 (t, J=7.0 Hz,3H); MS (ES) m/z: 329 (M+1)⁺; HPLC purity: 99.46% (220 nm), 100% (254nm).

19aj4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-methoxy-benzoicacid (D36)

To a solution of compound (D35) (0.1 g, 0.31 mmol) in methanol (2 mL)was added 2N NaOH (1 mL). The resulting mixture was stirred at rt O/N.The solvent was removed under reduced pressure to give crude product,which was dissolved in H₂O (1 mL) and acidified using 1N HCl. The solidobtained which was filtered and washed with ether (10 mL) to afford thetitle compound (D36) (78 mg, 86%) as a white solid. Mp 109.6-110.1° C.¹H NMR 400 MHz (DMSO-d₆) δ: 9.20 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.75(d, J=8.6 Hz, 1H), 7.18 (s, 1H), 7.15 (d, J=9.4 Hz, 1H), 6.80 (s, 1H),6.60 (d, J=8.6 Hz, 1H), 4.98 (s, 2H), 3.81 (s, 3H); MS (ES) m/z: 301(M+1)⁺; HPLC purity: 100% (220 nm), 99.79% (254 nm).

19ak2-Cyclopentyloxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile(D37)

To a solution of2-hydroxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile(D10) (200 mg, 0.75 mmol) in THF (50 mL) and DMF (20 mL) was added NaH(47 mg, 95%, 1.87 mmol) portion-wise. The mixture was stirred at roomtemperature for 5 minutes, followed by the slow addition of cyclopentyliodide (0.26 mL, 2.25 mmol). The reaction was stirred at roomtemperature for 24 hours. After the reaction, all volatile componentswere evaporated under vacuum. The residue was purified using silica gelcolumn chromatography, eluting with 25% EtOAc/hexane, afforded 36 mg ofthe title compound in 12.6% yield. ¹H NMR 400 MHz (DMSO-d₆) δ: 9.23 (s,1H), 7.78 (d, J=7.8 Hz, 1H) 7.69 (d, J=8.6 Hz, 1H), 7.17 (s, 1H), 7.10(dd, J=2.0, 8.2 Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.56 (dd, J=1.9, 8.6Hz, 1H), 4.96 (s, 2H), 4.95 (t, J=5.8 Hz, 1H), 1.95-1.55 (m, 8H); MS(ES) m/z: 336 (M+H)⁺; HPLC purity: 99.15% (220 nm), 99.62% (MaxPlot).

19al[2-Cyano-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenoxy]-aceticacid ethyl ester (D38)

To a solution of2-hydroxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile(D10) (300 mg, 1.12 mmol) in THF (50 mL) was added NaH (95 mg, 60%, 2.36mmol) portion-wise. The mixture was stirred at room temperature for 5minutes, followed by the slow addition of ethyl bromoacetate (0.262 mL,2.36 mmol). The reaction was heated at 70° C. overnight. After thecooling of the reaction solution to room temperature, the mixture wasfiltered. The filtrate was evaporated under vacuum. The residue waspurified using reverse phase chromatography, eluting from 5% MeOH/H₂O to90% MeOH/H₂O, afforded 320 mg of the title compound in 81% yield. ¹H NMR400 MHz (DMSO-d₆) δ: 9.25 (s 1H), 7.78 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.4Hz, 1H), 7.14 (d, J=1.6 Hz, 1H), 7.08 (dd, J=1.6, 7.6 Hz, 1H), 6.86 (d,J=2.0 Hz, 1H), 6.64 (dd, J=2.4, 8.8 Hz, 1H), 5.00 (s, 2H), 4.97 (s, 2H),4.13 (q, J=6.8 Hz, 2H), 1.16 (t, 6.8 Hz, 3H); MS (ES) m/z: 354 (M+H)⁺;HPLC purity: 99.11% (220 nm), 99.14% (254 nm).

19am[2-Cyano-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenoxy]-aceticacid (D39)

To a clear solution of[2-cyano-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenoxy]-aceticacid ethyl ester ((D38), 90 mg, 0.25 mmol) in THF (20 mL) was added LiOH(15.3 mg, 0.76 mmol) and water (5 mL). The resulting mixture was stirredat room temperature for 2 hours. Then 1 N HCl was slowly added to pH 2.The mixture was evaporated under vacuum. The residue was purified withreverse phase chromatography, eluting from 5% MeOH/H₂O to 90% MeOH/H₂O,afforded 48 mg of the title compound in 58% yield. ¹H NMR 400 MHz(CD₃OD) δ: 7.70 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.09 (s, 1H),7.05 (dd, J=1.9, 8.21 Hz, 1H), 6.66 (d, J=1.9 Hz, 1H), 6.63 (dd, J=1.9,8.6 Hz, 1H), 5.06 (s, 2H), 4.78 (s, 2H); MS (ES) m/z: 326 (M+H)⁺; HPLCpurity: 96.33% (220 nm), 96.44% (254 nm).

19an[2-Cyano-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenoxy]-aceticacid tert-butyl ester (D40)

To a solution of2-hydroxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile(D10) (200 mg, 0.75 mmol) in THF (50 mL) was added NaH (43 mg, 95%, 1.81mmol) portion-wise. The mixture was stirred at room temperature for 5minutes, followed by the slow addition of t-butyl bromoacetate (0.25 mL,1.65 mmol). The reaction was heated at 70° C. for 24 hours. After thecooling of the reaction solution to room temperature, the mixture wasfiltered. The filtrate was evaporated under vacuum. The residue waspurified using reverse phase chromatography, eluting from 5% MeOH/H₂O to90% MeOH/H₂O, afforded 36 mg of the title compound in 12.6% yield. ¹HNMR 400 MHz (DMSO-d₆) δ: 9.26 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.75 (d,J=8.6 Hz, 1H), 7.14 (s, 1H), 7.09 (dd, J=2.3, 8.2 Hz, 1H), 6.74 (d,J=2.3 Hz, 1H), 6.68 (dd, J=2.0, 8.6 Hz, 1H), 4.96 (s, 2H), 4.86 (s, 2H),1.37 (s, 9H); MS (ES) m/z: 380 (M−H)⁻; HPLC purity: 99.11% (220 nm),98.48% (254 nm).

General Procedure for Amide Coupling:

HATU (353 mg, 0.93 mmol) and diisopropylethylamine (0.32 mL, 1.86 mmol)were added to a solution of[2-cyano-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenoxy]-aceticacid ((D39), 150 mg, 0.46 mmol) in DMF (4 mL) at rt and stirred for 1minute. The corresponding amine (0.93 mmol) was added and the reactionmixture was stirred overnight at rt. The reaction mixture was dilutedwith distilled water (300 mL) and extracted with ethyl acetate (4×400mL). The organic extracts were combined, dried over Na₂SO₄ andconcentrated to give a crude oil. All crudes were purified by reversephase HPLC using a biphasic solvent system of 0.1% AcOH (aqueous) andacetonitrile which eluted as a gradient. Pure fractions obtained fromcolumn were combined and lyophilized to give final product in goodpurity.

19ao4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-(2-morpholin-4-yl-2-oxo-ethoxy)-benzonitrile(D41)

Following the general procedure, morpholine (80 μL, 0.93 mmol) wascoupled with[2-cyano-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenoxy]-aceticacid ((D39), 150 mg, 0.46 mmol) to give a crude oil containing (D41).Purification by reverse phase HPLC followed by lyophilization gave awhite solid of (D41) (38 mg, 21%). ¹H NMR 400 MHz (d₆-DMSO) δ: 9.32 (brs, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.21 (br s, 1H),7.15 (dd, J=9.0, 1.5 Hz, 1H), 6.90 (d, J=1.5 Hz, 1H), 6.65 (dd, J=8.5,1.5 Hz, 1H), 5.17 (s, 2H), 5.03 (s, 2H), 3.65-3.55 (m, 4H), 3.49-3.40(m, 4H); MS (ES) m/z: 395 (M+H)⁺; HPLC purity 96.02% (Maxplot), 97.64%(220 nm) and 97.18% (254 nm).

19ap4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-[2-(4-methyl-piperidin-1-yl)-2-oxo-ethoxy]-benzonitrile(D42)

Following the general procedure, 4-methyl piperidine (110 μL, 0.90 mmol)was coupled withcyano-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenoxy]-aceticacid ((D39), 97 mg, 0.30 mmol) to give a crude oil containing (D42).Purification by reverse phase HPLC followed by lyophilization gave awhite solid of (D42) (42 mg, 35%). ¹H NMR 400 MHz (d₆-DMSO) δ: 9.25 (brs, 1H), 7.78 (d, J=7.0 Hz, 1H), 7.73 (d, J=7.0 Hz, 1H), 7.13 (br s, 1H),7.08 (dd, J=7.5, 2.0 Hz, 1H), 6.74 (d, J=2.0 Hz, 1H), 6.62 (dd, J=7.5.2.0 Hz, 1H), 5.08 (d, J=10.0 Hz, 1H), 5.02 (d, J=10.0 Hz, 1H), 4.95 (s,2H), 4.22 (br d, J=10.5 Hz, 1H), 3.65 (br d, J=10.5 Hz), 2.93 (br t,J=10.5 Hz, 1H), 2.52 (br t, J=10.5 Hz, 1H), 1.63-1.50 (m, 3H), 1.08-0.96(m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.90-0.80 (m, 1H); MS (ES) m/z: 407(M+H)⁺; HPLC purity 99.51% (Maxplot), 99.12% (220 nm) and 98.77% (254nm).

19aq4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethoxy]-benzonitrilehexafluorophosphate (D43)

Following the general procedure, 4-methyl piperazine (150 μL, 0.90 mmol)was coupled withcyano-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenoxy]-aceticacid ((D39), 150 mg, 0.46 mmol) to give a crude oil containing (D43).Purification by reverse phase HPLC followed by lyophilization gave awhite hexafluorophosphate salt (D43) (40 mg, 16% purity). ¹H NMR 400 MHz(d₆-DMSO) δ: 9.65 (br s, 1H), 9.23 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.73(d, J=8.0 Hz, 1H), 7.13 (s, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.97 (s, 1H),6.55 (d, J=8.0 Hz, 1H), 5.17 (s, 2H), 4.97 (s, 2H), 3.50-2.76 (br m,5H), 3.35 (br s, 3H), 2.70 (br s, 3H); ¹⁹F NMR 376 MHz (d₆-DMSO)-70.6(d, J=714 Hz, 6F) ppm; MS (ES) m/z: 408 (M+H)⁺; HPLC purity 94.56%(Maxplot), 95.06% (220 nm) and 95.77% (254 nm).

19ar6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-pyridine-2,3-dicarboxylicacid dimethyl ester (D44)

1-Oxy-pyridine-2,3-dicarboxylic acid dimethyl ester (17)

A mixture of pyridine-2,3-dicarboxylic acid dimethyl ester (16, 2.0 g,10.24 mmol) and m-chloroperbenzoic acid (75% purity, 2.12 g, 12.28 mmol)in chloroform (50 mL) was stirred at room temperature for 16 h. Solidseparated was filtered and the filtrate was washed with saturated aq.NaHCO₃ (2×50 mL), dried over Na₂SO₄, filtered, and concentrated to givecrude product (2.3 g, quantitative) as yellow solid, which was used fornext step without purification. ¹H NMR 400 MHz (DMSO-d₆) δ: 8.65 (d,J=6.6 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.66 (dd, J=7.8, 6.6 Hz, 1H),3.91 (s, 6H); MS (ES) m/z: 212 (M+1)⁺.

6-Chloro-pyridine-2,3-dicarboxylic acid dimethyl ester (18)

Solution of 1-oxy-pyridine-2,3-dicarboxylic acid dimethyl ester (17, 4.0g, 18.94 mmol) in phosphorus oxychloride (30 mL) was heated at 115° C.for 3 h. After being cooled, the mixture was treated with ice-water (50mL) and chloroform (3×50 mL), basified with saturated aq. NaHCO₃ (3×50mL), and separated the layers. The chloroform layer was dried overNa₂SO₄, filtered, and concentrated to give crude product (4.0 g) asbrown oil, which was used for next step without purification. ¹H NMR 400MHz (DMSO-d₆) δ: 8.32 (d, J=8.2 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 3.85(s, 6H); MS (ES) m/z: 230 (M+1)⁺, 232 (M+3)⁺.

6-(4-Bromo-3-formyl-phenoxy)-pyridine-2,3-dicarboxylic acid dimethylester (19)

To a solution of 6-chloro-pyridine-2,3-dicarboxylic acid dimethyl ester(18, 4.0 g, 17.42 mmols) and 2-bromo-5-hydroxy-benzaldehyde (3.5 g,17.42 mmol) in DMF (30 mL) was added cesium carbonate (11.35 g, 34.84mmols). The resulting mixture was heated at 80° C. overnight. DMF wasremoved under reduced pressure, diluted with EtOAc (100 mL), washed withwater (2×25 mL) and brine (50 mL) solution. The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated to give crude productwhich was purified by column chromatography (Silica gel 20% EtOAc inhexane) to yield title compound 19 (1.14 g, 15%) as a light yellow oil.¹H NMR 400 MHz (DMSO-d₆) δ: 10.18 (s, 1H), 8.38 (d, J=8.6 Hz, 1H), 7.90(d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.55-7.52 (m, 1H), 7.36 (d, J=8.6 Hz,1H), 3.86 (s, 3H), 3.84 (s, 3H); MS (ES) m/z: 394 (M+1)⁺, 396 (M+3)⁺.

6-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pyridine-2,3-dicarboxylicacid dimethyl ester (20)

To a degassed solution (30 min with nitrogen) of6-(4-bromo-3-formyl-phenoxy)-pyridine-2,3-dicarboxylic acid dimethylester (19, 1.14 g, 2.89 mmol) in 1,4-dioxane (10 mL) was addedbis(pinacolato)diboron (1.10 g, 4.33 mmol), potassium acetate (0.85 g,8.67 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride (0.16 g,0.23 mmol). Degassed again (10 min with nitrogen), and the suspensionwas heated at 90° C. overnight. The mixture was passed through Celite®and concentrated under reduced pressure to give crude product, which waspurified by column chromatography (silica gel, 20% EtOAc in hexane) toyield the title compound 20 (0.85 g, 70%) as a colorless oil. ¹H NMR 400MHz (DMSO-d₆) δ: 10.39 (s, 1H), 8.39 (d, J=8.6 Hz, 1H), 7.85 (d, J=7.8Hz, 1H), 7.69 (s, 1H), 7.56-7.53 (m, 1H), 7.36 (d, J=8.6 Hz, 1H), 3.84(s, 3H), 3.79 (s, 3H), 1.35 (s, 12H).

19ar6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-pyridine-2,3-dicarboxylicacid dimethyl ester (D44)

To a solution of6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pyridine-2,3-dicarboxylicacid dimethyl ester (20, 0.77 g, 1.74 mmol) in absolute ethanol (10 mL)was added sodium borohydride (0.08 g, 2.09 mmol) at 0° C. After 1 h at0° C., 2 M HCl was added until pH is 2˜3. The solvent was removed underreduced pressure to give crude product, which was purified by reversephase prep HPLC using CH₃CN/H₂O (using neutral condition) as the eluentto yield the title compound (D44) (0.18 g, 30%) as a white solid afterlyophilization. Mp 67.5-69.2° C. ¹H NMR 400 MHz (DMSO-d₆) δ: 9.24 (s,1H), 8.33 (d, J=8.6 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.25-7.22 (m, 2H),7.15 (d, J=7.8 Hz, 1H), 4.98 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H); MS(ES) m/z: 344 (M+1)⁺; HPLC purity: 99.42% (Maxplot), 99.03% (220 nm),99.95% (254 nm).

19as3-Cyano-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-pyridine-2-carboxylicacid ethyl ester (D45)

3-Bromo-6-chloro-pyridine-2-carboxylic acid ethyl ester (22)

To a solution of 3-bromo-6-chloropicolinic acid (21, 8.0 g, 33.83 mmols)in a mixture of toluene (80 mL) and ethanol (40 mL) was added sulfuricacid (0.66 mL, 6.76 mmols). The reaction mixture was refluxed for 16 h,then allowed to cool, and partitioned between CHCl₃ (200 mL) andsaturated aq. NaHCO₃ (250 mL). The aqueous layer was extracted withCHCl₃ (2×100 mL), and the combined organic layers were dried overNa₂SO₄, filtered, and concentrated to give crude product which waspurified by column chromatography (Silica gel 10% EtOAc in hexane) toyield title compound 22 (9.0 g, quantitative) as transparent oil. ¹H NMR400 MHz (DMSO-d₆) δ: 8.31 (d, J=8.6 Hz, 1H), 7.68 (d, 1H, J=8.2 Hz),4.39 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).

3-Bromo-6-(4-bromo-3-formyl-phenoxy)-pyridine-2-carboxylic acid ethylester (23)

To a solution of 3-bromo-6-chloro-pyridine-2-carboxylic acid ethyl ester(22, 8.0 g, 30.24 mmol) and 2-bromo-5-hydroxy-benzaldehyde (7.29 g,36.29 mmol) in DMF (100 mL) was added cesium carbonate (22.6 g, 69.55mmol). The resulting mixture was heated at 80° C. overnight. DMF wasremoved under reduced pressure, and the residue was diluted with EtOAc(200 mL), washed with water (2×50 mL) and brine (50 mL) solution. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated to give crude product which was purified by columnchromatography (Silica gel 20% EtOAc in hexane) to yield title compound23 (4.0 g, 31%) as transparent oil. ¹H NMR 400 MHz (DMSO-d₆) δ: 10.18(s, 1H), 8.27 (d, J=8.6 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.65 (s, 1H),7.51 (dd, J=8.7, 2.9 Hz, 1H), 7.26 (d, J=8.9 Hz, 1H), 4.29 (q, J=7.1 Hz,2H), 1.25 (t, J=7.0 Hz, 3H); MS (ES) m/z: 430 (M+1)⁺.

6-(4-Bromo-3-formyl-phenoxy)-3-cyano-pyridine-2-carboxylic acid ethylester (24)

To a solution of3-bromo-6-(4-bromo-3-formyl-phenoxy)-pyridine-2-carboxylic acid ethylester (23, 1.8 g, 4.19 mmol) in DMF (6 mL) was added CuCN (0.75 g, 8.38mmol) in portions at 130° C. and heated for 4 hour. The mixture wascooled to room temperature and ethyl acetate (100 mL) was added. Themixture was stirred for 10 minutes, filtered, and washed with ethylacetate (2×50 mL). The filtrate was washed with water (2×50 mL) andbrine (50 mL), dried over anhydrous sodium sulfate, filtered andevaporated in vacuo. The residue was purified by column chromatography(25% ethyl acetate/hexanes) to yield compound 24 (0.3 g, 19%) as a whitesolid. ¹H NMR 400 MHz (DMSO-d₆) δ: 10.20 (s, 1H), 8.51 (d, J=8.6 Hz,1H), 7.91 (d, J=8.9 Hz, 1H), 7.76 (s, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.55(dd, J=8.5, 2.7 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H);MS (ES) m/z: 377 (M+1)⁺.

3-Cyano-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pyridine-2-carboxylicacid ethyl ester (25)

To a degassed solution (30 min with nitrogen) of6-(4-bromo-3-formyl-phenoxy)-3-cyano-pyridine-2-carboxylic acid ethylester (24, 0.30 g, 0.79 mmol) in 1,4-dioxane (6 mL) was addedbis(pinacolato)diboron (0.30 g, 1.19 mmol), potassium acetate (0.23 g,2.39 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride (0.03 g, 0.03 mmol). Degassed again (10 min nitrogen), and thesuspension was heated at 80° C. overnight. The mixture was passedthrough Celite® and concentrated under reduced pressure to give crudeproduct, which was purified by column chromatography (silica gel, 25%EtOAc in hexane) to yield the title compound 25 (0.11 g, 29%) as acolorless oil. ¹H NMR 400 MHz (DMSO-d₆) δ: 10.38 (s, 1H), 8.51 (d, J=8.9Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.76 (s, 1H), 7.51 (d, J=2.7 Hz, 1H),7.49 (d, J=8.5 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 1.39 (s, 12H), 1.21 (t,J=7.0 Hz, 3H).

19as3-Cyano-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-pyridine-2-carboxylicacid ethyl ester (D45)

To a solution of3-cyano-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pyridine-2-carboxylicacid ethyl ester (25, 0.11 g, 0.23 mmol) in methanol (5 mL) was addedsodium borohydride (0.01 g, 0.27 mmol) at 0° C. After 1 h at 0° C., 2 MHCl was added until pH is 2˜3. The solvent was removed under reducedpressure to give crude product, which was purified by reverse phase prepHPLC using CH₃CN/H₂O (0.1% AcOH) as the eluent to yield the titlecompound (D45) (0.08 g, 20%) as a white solid after lyophilization. Mp204-206° C. ¹H NMR 400 MHz (DMSO-d₆) δ: 9.26 (s, 1H), 8.47 (d, J=9.0 Hz,1H), 7.80 (d, J=9.4 Hz, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.32 (s, 1H),7.24-7.19 (m, 1H), 4.99 (s, 2H), 4.32-4.23 (m, 2H), 1.39-1.20 (m, 3H);MS (ES) m/z: 325 (M+1)⁺; HPLC purity: 96.01% (Maxplot), 98.13% (220 nm),97.47% (254 nm).

19at6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-methoxy-nicotinonitrile(D46) and 19au2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-6-methoxy-nicotinonitrile(D47)

6-Chloro-2-methoxy-nicotinonitrile and2-Chloro-6-methoxy-nicotinonitrile (27 and 28)

To a solution of 2,6-dichloro-nicotinonitrile (26, 5.0 g, 28.90 mmol) inmethanol (25 mL) was added sodium methoxide (25% solution in methanol,6.24 mL, 28.90 mmol) slowly at 0° C. and stirred for 16 h at roomtemperature. Methanol was distilled off and the residue was diluted withEtOAc (150 mL), washed with water (2×50 mL) and brine (50 mL), driedover Na₂SO₄, filtered, and concentrated to give crude mixture, which wasrecrystallized from ether to give inseparable mixture of compounds 27and 28 in a ratio of 1:2 (4.8 g, quantitative) as white solid. ¹H NMR400 MHz (DMSO-d₆) δ: 8.30 (d, J=8.2 Hz, 1H), 8.27 (d, J=8.6 Hz, 1H),7.31 (d, J=7.7 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 3.98 (s, 3H), 3.92 (s,3H).

6-(4-Bromo-3-formyl-phenoxy)-2-methoxy-nicotinonitrile and2-(4-Bromo-3-formyl-phenoxy)-6-methoxy-nicotinonitrile (29 and 30)

To a mixture of 6-chloro-2-methoxy-nicotinonitrile and2-chloro-6-methoxy-nicotinonitrile (27 and 28, 5.0 g, 29.65 mmol) and2-bromo-5-hydroxy-benzaldehyde (5.96 g, 29.65 mmol) in DMF (100 mL) wasadded potassium carbonate (6.14 g, 44.47 mmol). The resulting mixturewas heated at 80° C. overnight. DMF was removed under reduced pressure,residue was dissolved in EtOAc (150 mL), washed with water (2×50 mL) andbrine (50 mL) solution, dried over Na₂SO₄, filtered, and concentrated togive brown oil, which was recrystallized from diethyl ether (50 mL) togive inseparable mixture of compounds 29 and 30 in a ratio of 1:2 (5.8g, 60%) as white solid. ¹H NMR 400 MHz (DMSO-d₆) δ: 10.17 (s, 2H),8.28-8.23 (m, 2H), 7.87 (dd, J=8.5, 2.7 Hz, 2H), 7.75 (d, J=2.7 Hz, 1H),7.71 (d, J=3.1 Hz, 1H), 7.62-7.55 (m, 2H), 6.79 (d, J=8.2 Hz, 1H), 6.73(d, J=8.6 Hz, 1H), 3.71 (s, 3H), 3.61 (s, 3H); MS (ES) m/z: 335 (M+1)⁺.

6-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methoxy-nicotinonitrileand2-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-6-methoxy-nicotinonitrile(31 and 32)

To a degassed solution (30 min with nitrogen) of6-(4-bromo-3-formyl-phenoxy)-2-methoxy-nicotinonitrile and2-(4-bromo-3-formyl-phenoxy)-6-methoxy-nicotinonitrile (29 and 30, 4.80g, 14.40 mmol) in 1,4-dioxane (70 mL) was added bis(pinacolato)diboron(5.48 g, 21.61 mmol), potassium acetate (4.24 g, 43.20 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride (0.54 g,0.72 mmol). Degassed again (10 min with nitrogen), and the suspensionwas heated at 90° C. overnight. The mixture was passed through Celiteand concentrated under reduced pressure to give crude product, which waspurified by column chromatography (silica gel, 25% EtOAc in hexane) toyield the title compounds 31 and 32 in a ratio of 1:1.5 (4.60 g, 85%) asa colorless oil. ¹H NMR 400 MHz (DMSO-d₆) δ: 10.37 (s, 2H), 8.28-8.24(m, 2H), 7.83-7.57 (m, 4H), 7.64-7.57 (m, 2H), 6.80-6.73 (m, 2H), 3.71(s, 3H), 3.61 (s, 3H), 1.39 (s, 24H).

19at6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-methoxy-nicotinonitrile(D46) and 19au2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-6-methoxy-nicotinonitrile(D47)

To a solution of6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methoxy-nicotinonitrileand2-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-6-methoxy-nicotinonitrile(31 and 32, 2.6 g, 6.83 mmol) in methanol (15 mL) was added sodiumborohydride (0.31 g, 8.19 mmol) at 0° C. and left at the sametemperature for 1 h. 2 M HCl was added until pH reached 2˜3. The solventwas removed under reduced pressure to give a mixture of regioisomerswhich were separated by chiral column (Chiralcel_OJ_(—)10 um_(—)4-6×250mm, eluting with 90 hexane/5iPrOH/5EtOH) to yield the title compounds(D46) (1.70 g, 58%) and (D47) (0.40 g, 23%) as white solids afterlyophilization.

19at6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-methoxy-nicotinonitrile(D46)

¹H NMR 400 MHz (DMSO-d₆) δ: 9.24 (s, 1H), 8.21 (d, J=8.2 Hz, 1H), 7.77(d, J=7.8 Hz, 1H), 7.29 (s, 1H), 7.19 (d, J=8.6 Hz, 1H), 6.64 (d, J=8.2Hz, 1H), 4.97 (s, 2H), 3.74 (s, 3H); MS (ES) m/z: 283 (M+1)⁺; HPLCpurity: 99.77% (Maxplot), 99.27% (220 nm), 99.77% (254 nm).

19au2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-6-methoxy-nicotinonitrile(D47)

¹H NMR 400 MHz (DMSO-d₆) δ: 9.24 (s, 1H), 8.25 (d, J=7.2 Hz, 1H), 7.78(d, J=7.8 Hz, 1H), 7.32 (s, 1H), 7.25-7.23 (m, 1H), 6.73 (d, J=8.6 Hz,1H), 5.00 (s, 2H), 3.63 (s, 3H); MS (ES) m/z: 283 (M+1)⁺; HPLC purity:100% (Maxplot), 98.76% (200 nm), 99.59% (254 nm).

19av Ethyl5-chloro-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate(D48)

The title compound was prepared by procedures similar to that describedbelow for D60.

Mp 149-153° C. ¹H NMR (300 MHz, DMSO-d₆): δ 9.24 (s, 1H), 8.57 (d, J=1.8Hz, 1H), 8.42 (dd, J=2.1 & 0.6 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.25 (d,1H), 7.17 (dd, J=7.8 & 2.1 Hz, 1H), 4.97 (s, 2H), 4.31 (q, J=7.2 Hz, 2H)and 1.30 (t, J=7.2 Hz, 3H) ppm. Purity (HPLC): 95% at 220 nm and 95% at254 nm. MS: m/z=334 (M+1, ESI+) and m/z=332 (M−1, ESI−).

19aw5-Chloro-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinicacid (D49)

Hydrolysis of ethyl5-chloro-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate(0.9 g, 2.7 mmol) with 1N NaOH (11 mL) in MeOH (50 mL) overnight at r.t.followed by acidification with 6N HCl, work-up and recrystallizationfrom EtOAc and hexane afforded off-white solid of the title carboxylicacid compound (0.76 g, 2.49 mmol, yield 92%).

Mp 185-190° C. (dec.). ¹H NMR (300 MHz, DMSO-d₆): δ 13.50 (s, 1H), 9.23(s, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 7.77 (d, J=7.8Hz, 1H), 7.25 (d, J=1.5 Hz, 1H), 7.16 (dd, J=7.8 & 1.5 Hz, 1H) and 4.97(s, 2H) ppm. Purity (HPLC): >95% at 254 nm. MS: m/z=306 (M+1, ESI+) andm/z=260 (M−45, ESI−).

19ax 5-(2-Fluoro-4-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole(D50)

A mixture of 4-bromo-3-(1,3-dioxolan-2-yl)phenol (7.1 g, 29 mmol, 1 eq),methyl 3,4-difluorobenzorate (5 g, 29 mmol, 1 eq), potassium carbonate(6 g, 43.5 mmol, 1.5 eq) in DMF (29 mL). Reaction was stirred at 100° C.over night. TLC showed that reaction was completed. After cooling toroom temperature, the residue was removed by filtration. The residue waswashed with EtOAc. The organics were combined and concentrated via Rotavapor. The residue was poured into EtOAc and water. The organic layerswas separated and washed with brine and dried over sodium sulfateanhydrous. Filter and concentrated to get methyl4-(4-bromo-3-(1,3-dioxolan-2-yl)phenoxy)-3-fluorobenzoate as crude,light brown oil, which was used for next step without purification.

To a solution of methyl4-(4-bromo-3-(1,3-dioxolan-2-yl)phenoxy)-3-fluorobenzoate in 30 mL ofTHF was added 20 ml of 3M HCl (made from 6M HCl and water 1:1), refluxedfor 2 hour. TLC showed no SM (Hexane:EtOAc 7:3). The reaction was cooledto RT. Add 1N NaOH (60 ml), Rota vapor to remove half of the solvent,extracted with EtOAc. The organics were washed with water, brine, driedover Na2SO4, filtered, and concentrated to get light brown oil. Standbyover weekend to get solidified solid. Filtered, washed with Hexane/EtOActo collect methyl 4-(4-bromo-3-formylphenoxy)-3-fluorobenzoate as aoff-white powder (10.2 g, 100%)

To a solution of methyl 4-(4-bromo-3-formylphenoxy)-3-fluorobenzoate;(10 g, 28.3 mmol), KOAc (8.33 g, 84.9 mmol), bis(pinacolato)diboron(8.63 g, 34 mmol) in anhydrous 1,4-dioxane (120 mL) was addedPdCl₂(dppf)₂ (578 mg; 2.5 mol % CAS #72287-26-4, Aldrich catalog#379670). The reaction mixture was degassed with N₂, and then heated at80° C. with magnetic stirring. The reaction was monitored with TLC andwas completed overnight. The mixture was cooled to room temperature,filtered through Celite and washed with ethyl acetate and thenevaporated. The residue was dissolved in minimum EtOAc and passedthrough a very short but big silica gel column eluted with a mixedsolvent of hexane:EtOAc (3:1, v/v) to remove dark color giving lightyellow oil. Chromatography on silica gel again (Hexane/EtOAc 7:3). Thefirst portion is white solid, NMR indicated as bis(pinacolato)diboron(no aromatic signals). The product was collected and concentrated toafford methyl3-fluoro-4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzoateas colorless oil (9.5 g, 84%).

¹H NMR (DMSO-d6, 300 MHz): δ=10.38 (s, 1H), 7.91 (dd, J=2.1, 13.2 Hz,1H), 7.82 (d, J=7.8 Hz, 2H), 7.42 (d, J=2.7 Hz, 2H), 7.32 (d, J=8.4 Hz,1H), 3.85 (s, 3H), and 1.32 (s, 12H) ppm.

To a solution of methyl3-fluoro-4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzoate(5 g, 12.5 mmol) in MeOH (125 mL) was added NaBH₄ (709 mg; 18.75 mmol)in portions under N2 at 0° C. in an ice-bath. The reaction was stirredat 0° C. to room temperature. The reaction was monitored with TLC andwas completed overnight. The mixture was cooled to rt. Solvent wasevaporated to half volume via Rota vapor. The mixture was then cooled to0° C., and quenched by adding water (12 mL) following by adding 6 N HCl(12 mL). Stirred at rt for 30 min, white Solid precipitated out.Filtered. The solid was gummy. The solid was suspended in water,sonicated for 1 hr. Filtered, washed with more water. Filtered, dried toget target compound as a white solid (2.1 g, 56%).

¹H NMR (DMSO-d6, 300 MHz): δ=9.19 (s, 1H), 7.88 (dd, J=1.8, 11.1 Hz,1H), 7.80 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.21 (d, J=8.4 Hz,1H), 7.07 (d, J=8.4 Hz, 2H), 4.93 (s, 2H), and 3.84 (s, 3H)

19ay 5-(2-Fluoro-4-ethoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole(D51)

This compound was obtained in a similar manner to Example 19ax (D50)from ethyl 3,4-difluorobenzorate and 4-bromo-3-formylphenol.

ESI-MS (m/z) 315 (M−H)

19az5-(2,6-Difluoro-4-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole(D52)

This compound was obtained in a similar manner to Example 19ax (D50)from methyl 3,4,5-trifluorobenzorate and 4-bromo-3-formylphenol.

ESI-MS (m/z) 319 (M−H)⁻

19ba5-(5-Chloro-2-fluoro-4-ethoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole(D53)

This compound was obtained in a similar manner to Example 19ax (D50)from ethyl 2-chloro-4,5-difluorobenzorate and 4-bromo-3-formylphenol.

ESI-MS (m/z) 349 (M−H)⁻

19bb5-(4-Ethoxycarbonyl-2-trifluoromethylphenoxy)-1-hydroxy-2,1-benzoxaborole(D54)

This compound was obtained in a similar manner to Example 19ax (D50)from ethyl 4-fluoro-3-trifluoromethylbenzorate and4-bromo-3-formylphenol.

ESI-MS (m/z) 365 (M−H)⁻

19bc5-(2-Fluoro-4-isopropyloxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole(D55)

This compound was obtained in a similar manner to Example 19ax (D50)from isopropyl 3,4-difluorobenzorate and 4-bromo-3-formylphenol.

ESI-MS (m/z) 329 (M−H)⁻

19bd5-(2,6-Difluoro-4-ethoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole(D56)

This compound was obtained in a similar manner to Example 19ax (D50)from ethyl 3,4,5-trifluorobenzorate and 4-bromo-3-formylphenol.

ESI-MS (m/z) 333 (M−H)⁻

19be 5-(3-Chloro-4-ethoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole(D57)

This compound was obtained in a similar manner to Example 19ax (D50)from ethyl 2-chloro-4-fluorobenzorate and 4-bromo-3-formylphenol.

ESI-MS (m/z) 331 (M−H)⁻

19bf5-(2-Chloro-5-fluoro-4-ethoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole(D58)

This compound was obtained in a similar manner to Example 19ax (D50)from ethyl 5-chloro-2,4-difluorobenzorate and 4-bromo-3-formylphenol.

ESI-MS (m/z) 349 (M−H)⁻

19bi(4-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)phenyl)methanaminiumchloride (D59)

The title compound was synthesized by the same procedure as describedabove for the preparation of its regional isomer. Yield 66.7%.

Mp.>250° C. ¹H NMR (DMSO-d₆, 300 MHz): δ 9.18 (s, 1H), 8.43 (br. s, 3H),7.74 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.7 Hz, 2H), 7.08 (d, J=8.7 Hz, 1H),6.98-6.94 (m, 2H), 4.91 (s, 2H) and 3.99 (br. q, J=4.8 Hz, 2H) ppm.Purity (HPLC): 92.2% at 220 nm and 94.9% at 254 nm. MS: m/z=256 (M+1,ESI+) and m/z=255 (M−, ESI−).

19bj Ethyl6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate (D60)

To a mixture of ethyl 6-chloronicotinate (18.6 g, 0.1 mol) and2-bromo-5-hydroxy benzaldehyde (20.1 g, 0.1 mol) in dry DMF (200 mL) wasadded K₂CO₃ (20.8 g, 1.5 eq) under nitrogen atmosphere and the mixturewas stirred at 65-80° C. for 30.5 h. After being cooled to roomtemperature, the mixture was filtered, evaporated and pumped overnightto give brown oil (38.26 g) with 81.5% coupling conversion to ethyl6-(4-bromo-3-formylphenoxy)nicotinate as indicated by NMR.

¹H NMR (300 MHz, DMSO-d₆): δ 10.17 (s, 1H), 8.66-8.65 (m, 1H), 8.33 (dd,J=8.7&2.4 Hz, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.60 (d, J=2.7 Hz, 1H), 7.50(dd, J=8.4&2.7 Hz, 1H), 7.23 (dd, J=8.7& 0.6 Hz, 1H), 4.30 (q, J=7.2 Hz,2H) and 1.29 (t, J=7.2 Hz, 3H) ppm.

To the solution of the resulting oil intermediate in 1,4-dioxane (450mL) was added bis-pinacol-diboron (30.5 g, 0.12 mol), KOAc (29.5 g, 0.3mol) and PdCl₂(dppf)₂ (1.95 g, 2.5% mol), and the mixture was degassedwith N₂ and heated at 80° C. for 14 h with stirring. The resulting darkmixture was filtered and evaporated. The residue was dissolved inminimum EtOAc, passed through a short silica gel column eluted withhexane:EtOAc (2:1) to remove the dark color giving brown oil (46.4 g)mainly containing ethyl6-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinate.

¹H NMR (300 MHz, DMSO-d₆): δ 10.39 (s, 1H), 8.67-8.65 (m, 1H), 8.35-8.31(m, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.64 (d, J=2.7 Hz, 1H), 7.50 (dd, J=7.8& 2.7 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 1.34 (s,12H) and 1.29 (t, J=7.2 Hz, 3H) ppm.

To the solution of the pinacolboron aldehyde (46.4 g) in EtOH (450 mL,200 proof) at 0° C. was added NaBH₄ (5 g) in portions and the mixturewas stirred overnight with slow increasing to room temperature. Themixture was cooled with ice bath again and water (50 mL) was added andfollowed with slow addition of 6N HCl (50 mL). After being stirred for30 min, the mixture was evaporated to remove EtOH and then water (200mL) was added, neutralized with NaHCO₃-saturated water. The mixture wasextracted with EtOAc, concentrated and loaded to a short and big silicagel column eluted with hexane:EtOAc (2:1, v/v) to remove dark impurity.The oil obtained contained pinacol impurity that also complicates theproton NMR spectrum. The oil was dissolved in minimum acetone, and thenwater was added slowly with sonication at same time to participate thesolid product. The solid was collected by filtration and washed withpentane and hexane, dried overnight under high vacuum to give ethyl6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate as acream solid (17.84 g) in 59.6% overall yield (3 steps).

M.p. 110-113° C. ¹H NMR (300 MHz, DMSO-d₆): δ 9.21 (s, 1H), 8.68 (d,J=2.4 Hz, 1H), 8.30 (dd, J=8.4 & 2.1 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H),7.21 (d, J=1.5 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 7.12 (dd, J=7.8 & 2.1Hz, 1H), 4.97 (s, 2H), 4.30 (q, J=7.5 Hz, 2H) and 1.29 (t, J=7.5 Hz, 3H)ppm. Purity (HPLC): 95.3% at 220 nm and 95.4% at 254 nm. MS: m/z=300(M+1, ESI+) and m/z=298 (M−1, ESI−).

19bk 6-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinicacid (D61)

The title bis-acid compound was prepared by hydrolysis of thecorresponding carboxylic acid ethyl ester. Ethyl6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate (2.99g, 10 mmol) was dissolved in freshly opened THF (100 mL), and 1N NaOH(38 mL) was added. The mixture was stirred at room temperature under N₂overnight. Then 6N HCl (6.5 mL) was added, rotary evaporated to removeTHF, filtered and washed with water and then hexane. The solid was driedovernight under high vacuum to afford the title bis-acid compound (2.57g, 9.48 mmol, yield 94.8%) as a slightly brown solid.

M.p.>200° C. ¹H NMR (300 MHz, DMSO-d₆): δ 13.21 (s, 1H), 9.21 (s, 1H),8.65 (d, J=2.1 Hz, 1H), 8.28 (dd, J=8.4 & 2.4 Hz, 1H), 7.76 (d, J=7.8Hz, 1H), 7.21 (d, J=1.5 Hz, 1H), 7.14-7.11 (m, 2H) and 4.97 (s, 2H) ppm.Purity (HPLC): 97.2% at 220 nm and 97.8% at 254 nm. MS: m/z=272 (M+1,ESI+) and m/z=270 (M−1, ESI−).

19blN,N-diethyl-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinamide(D62)

To the solution of6-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinic acid(0.813 g, 3 mmol) in anhydrous DMF (70 mL) was added diethylamine (3.2mL, 30 mmol) and DIPEA (1.6 mL, 9 mmol) under N₂. The mixture was cooledwith ice bath and a coupling agent PyCloP (Aldrich #26564, 1.4 g, 3.3mmol) was added. The reaction mixture was stirred at 0° C. for 10 minand at room temperature overnight, and then rotary evaporated. Theresidue was dissolved in EtOAc and washed with water, evaporated andpurified by flash column chromatography over silica gel eluted withEtOAc to provide the title amide compound as a white solid (0.92 g, 2.82mmol, yield 94%).

Mp 85-95° C. ¹H NMR (300 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.15 (dd, J=2.4& 0.6 Hz, 1H), 7.86 (dd, J=8.7 & 2.4 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H),7.19 (dd, J=2.1 & 0.6 Hz, 1H), 7.13-7.07 (m, 2H) and 4.96 (s, 2H),3.48-3.12 (broad m, 4H) and 1.16-1.02 (broad s, 6H) ppm. Purity (HPLC):97.0% at 220 nm and 96.9% at 254 nm. MS: m/z=327 (M+1, ESI+) and m/z=325(M−1, ESI−).

19bmN-Ethyl-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinamide(D63)

The title compound was synthesized from the corresponding carboxylicacid using the same methodology described for the diethyl amideanalogue. Yield 78.3%.

Mp 100-120° C. (hydroscopic). ¹H NMR (300 MHz, DMSO-d₆): δ 9.20 (s, 1H),8.57 (d, J=2.1 Hz, 1H), 8.54 (broad t, J=5.4 Hz, 1H), 8.23 (dd, J=8.4 &2.4 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.12-7.08(m, 2H), 4.96 (s, 2H), 3.32-3.22 (m, 2H) and 1.10 (t, J=7.2 Hz, 3H) ppm.Purity (HPLC): 97.2% at 220 nm and 98.1% at 254 nm. MS: m/z=299 (M+1,ESI+) and m/z=297 (M−1, ESI−).

19bn 5-(5-(Hydroxymethyl)pyridin-2-yloxy)benzo[c][1,2]oxaborol-1 (3H)-ol(D64)

Reduction of ethyl6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate (2 g,6.68 mmol) in THF (130 mL) with Super Hydride (LiEt₃BH, 1M in THF, 26.7mL) at 0° C. to r.t. overnight with normal work-up gave the titlealcohol as white solid (1.03 g, yield 60%).

Mp 210-212° C. ¹H NMR (300 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.08-8.07 (m,1H), 7.81-7.78 (m, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.09 (s, 1H), 7.05-7.01(m, 2H), 5.28 (broad s, 1H), 4.94 (s, 2H) and 4.46 (s, 2H) ppm. Purity(HPLC): 96.5% at 220 nm and 98.3% at 254 nm. MS: m/z=258 (M+1, ESI+) andm/z=256 (M−1, ESI−).

19bo Methyl6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate (D65)

The mixture of the corresponding carboxylic acid (0.8 g, 2.95 mmol) and96% H₂SO₄ (1 g) in MeOH (130 mL) was refluxed overnight under N₂. Normalwork-up and flash column chromatography over silica gel eluted withhexane:EtOAc (1:1, v/v) provided the title methyl ester compound as awhite solid (0.127 g, yield 15.1%).

Mp 156-158° C. ¹H NMR (300 MHz, DMSO-d₆): δ 9.22 (s, 1H), 8.68 (dd,J=2.4 & 0.6 Hz, 1H), 8.31 (dd, J=8.7 & 2.4 Hz, 1H), 7.76 (d, J=7.8 Hz,1H), 7.22 (d, J=1.2 Hz, 1H), 7.17-7.11 (m, 2H), 4.97 (s, 2H) and 3.84(s, 3H) ppm. Purity (HPLC): 98.0% at 220 nm and 100% at 254 nm. MS:m/z=286 (M+1, ESI+) and m/z=284 (M−1, ESI−).

19bp n-Propyl6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate (D66)

The mixture of the corresponding carboxylic acid (0.5 g, 1.84 mmol) anda coupling agent CDI (0.66 g, 4.06 mmol, 2.2 eq) in a mixed solvent ofCH₂Cl₂ (50 mL), THF (30 mL) and DMF (40 mL) was stirred at r.t.overnight under N₂. Then anhydrous n-PrOH (30 mL) was injected into themixture, and catalytic amount of NaH (60%, 10 mg) was added. The mixturewas refluxed under N₂ for 2 h and then evaporated. The residue wasdissolved in EtOAc, washed with 0.5N HCl, then with NaHCO₃ solution(pH=8), dried and evaporated. The sticky solid was dissolved in minimumacetone followed by addition of hexane with sonication and cooling togenerate the title n-propyl ester product as an off-white solid (0.354g, 1.13 mmol, yield 61.3%).

Mp 89-94° C. ¹H NMR (300 MHz, DMSO-d₆): δ 9.22 (s, 1H), 8.69 (d, J=2.4Hz, 1H), 8.31 (dd, J=8.7 & 2.7 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.22 (s,1H), 7.17-7.12 (m, 2H), 4.97 (s, 2H), 4.22 (t, J=6.3 Hz, 2H), 1.70(sextet, J=6.9 Hz, 2H) and 0.94 (t, J=7.2 Hz, 3H) ppm. Purity (HPLC):98.3% at 220 nm and 98.3% at 254 nm. MS: m/z=314 (M+1, ESI+) and m/z=312(M−1, ESI−).

19bq Isopropyl6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate (D67)

The title isopropyl ester compound was prepared by adapting theprocedure described above for the n-propyl ester with increase ofrefluxing time to 4 h. Yield 71.8%.

Mp 95-101° C. ¹H NMR (300 MHz, DMSO-d₆): δ 9.21 (s, 1H), 8.66 (d, J=2.4Hz, 1H), 8.29 (dd, J=8.7 & 2.1 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.21 (d,J=1.8 Hz, 1H), 7.16-7.11 (m, 2H), 5.12 (septet, J=6.0 Hz, 1H), 4.97 (s,2H) and 1.30 (d, J=6.3 Hz, 6H) ppm. Purity (HPLC): 98.2% at 220 nm and96.6% at 254 nm. MS: m/z=314 (M+1, ESI+) and m/z=312 (M−1, ESI−).

19br n-Butyl6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate (D68)

The title n-butyl ester compound was prepared by adapting the proceduredescribed above for the n-propyl ester with increase of refluxing timeto 4 h. Yield 68.5%.

Mp 75-80° C. ¹H NMR (300 MHz, DMSO-d₆): δ 9.22 (s, 1H), 8.68-8.67 (m,1H), 8.32-8.29 (dm, J_(d)=8.7 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.22 (s,1H), 7.17-7.12 (m, 2H), 4.97 (s, 2H), 4.26 (t, J=6.3 Hz, 2H), 1.66(pentatet, J=7.5 Hz, 2H), 1.39 (sextet, J=7.5 Hz, 2H) and 0.90 (t, J=7.5Hz, 3H) ppm. Purity (HPLC): 100% at 220 nm and 100% at 254 nm. MS:m/z=328 (M+1, ESI+).

19bs6-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinaldehyde(D69)

Coupling reaction of 6-chloronicotinaldehyde (5.4 g, 38.15 mmol) and4-bromo-3-(hydroxymethyl)phenol (8.15 g, 38.15 mmol) in the presence ofK₂CO₃ (8.5 g, 1.5 eq) in DMF (100 mL) for 2 h at 100° C. under N₂ gavethe desired 6-(4-bromo-3-(hydroxymethyl)phenoxy)nicotinaldehyde (8.03 g,26.1 mmol, yield 68.3%) as a white solid after silica gel columnpurification (hexane:EtOAc=3:1, v/v).

¹H NMR (300 MHz, DMSO-d₆): δ 9.98 (s, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.27(ddd, J=8.7 & 2.4 & 0.6 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.29 (d, J=2.4Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 7.07 (dd, J=8.1 & 2.4 Hz, 1H), 5.54 (t,J=5.4 Hz, 1H) and 4.50 (d, J=5.4 Hz, 2H) ppm.

THP protection of 6-(4-bromo-3-(hydroxymethyl)phenoxy)nicotinaldehyde(2.4 g, 7.78 mmol) with 3,4-dihydro-2H-pyran (2.2 mL) catalyzed with(1S)-(+)-10-camphorsulfonic acid in CH₂Cl₂ (80 mL) at r.t. for 1 hprovided the desired6-(4-bromo-3-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)nicotinaldehydeas colorless oil (3.07 g, 7.8 mmol, yield 100%) after silica gel columnpurification (hexane:EtOAc=3:1, v/v).

¹H NMR (300 MHz, DMSO-d₆): δ 9.98 (s, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.27(ddd, J=8.4 & 2.4 & 0.6 Hz, 1H), 7.68 (dd, J=8.4 & 0.6 Hz, 1H), 7.31 (d,J=2.4 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.12 (dd, J=8.4 & 3.0 Hz, 1H),4.75-4.74 (m, 1H), 4.70 (d, J=13.5 Hz, 1H), 4.48 (d, J=13.5 Hz, 1H),3.80-3.72 (m, 1H), 3.50-3.44 (m, 1H) and 1.80-1.40 (m, 6H) ppm.

Catalytic boronylation of6-(4-bromo-3-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)nicotinaldehyde(3.07 g, 7.83 mmol) with bis-pinacol-diboron (3.05 g, 12 mmol), KOAc(2.3 g, 23.5 mmol) and PdCl₂(dppf)₂ (0.163 g, 2.5% mmol) in 1,4-dioxane(100 mL) at 80° C. overnight under N₂ afforded the desired6-(3-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinaldehydeas oil (3 g, 6.83 mmol, yield 87.2%) after silica gel columnpurification (hexane:EtOAc=3:1, v/v).

¹H NMR (300 MHz, DMSO-d₆): δ 9.98 (s, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.27(dd, J=8.7 & 2.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.24-7.21 (m, 2H),7.10 (dd, J=8.4 & 2.4 Hz, 1H), 4.82 (d, J=12.9 Hz, 1H), 4.70-4.66 (m,2H), 3.79-3.72 (m, 1H), 3.47-3.40 (m, 1H), 1.75-1.43 (m, 6H) and 1.29(s, 12H) ppm.

Hydrolysis and simultaneous cyclization of6-(3-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)nicotinaldehyde(3 g, 6.83 mmol) in acidic aqueous EtOH under N₂ during a long weekendproduced the desired cyclic boronic acid6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinaldehyde asa white solid (1.12 g, 4.39 mmol, yield 64.3%) after a normal work-upwithout column chromatography.

Mp 179-182° C. ¹H NMR (300 MHz, DMSO-d₆): δ 9.98 (s, 1H), 9.23 (s, 1H),8.69 (d, J=2.4 Hz, 1H), 8.26 (ddd, J=8.4 & 2.4 & 0.9 Hz, 1H), 7.77 (d,J=8.1 Hz, 1H), 7.24-7.21 (m, 2H), 7.15 (dd, J=8.1 & 1.2 Hz, 1H) and 4.98(s, 2H) ppm. Purity (HPLC): 95% at 220 nm and 95% at 254 nm. MS: m/z=256(M+1, ESI+) and m/z=254 (M−1, ESI−).

19bt(Z)-N-((6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)pyridin-3-yl)methylene)-2-methylpropan-2-amineoxide (D70)

Reaction of the aldehyde cyclic boronic acid6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-yloxy)nicotinaldehyde(0.18 g, 0.7 mmol) with t-BuNHOH AcOH salt (0.25 g, 2 eq) and silica gel(0.5 g) in EtOH (30 mL) at r.t. overnight under N₂ generated the desiredtitle nitronyl cyclic boronic acid compound as white solid (0.1985 g,0.6085 mmol, yield 86.9%) after filtration, evaporation andrecrystallization from EtOAc and hexane with sonication.

Mp 156-164° C. 1H NMR (300 MHz, DMSO-d₆): δ 9.18 (s, 1H), 9.02 (d, J=2.1Hz, 1H), 8.90 (dd, J=8.7 & 2.1 Hz, 1H), 7.92 (s, 1H), 7.75 (d, J=8.1 Hz,1H), 7.15 (d, J=2.1 Hz, 1H), 7.11-7.06 (m, 2H), 4.96 (s, 2H) and 1.48(s, 12H) ppm. Purity (HPLC): >95% at 220 nm and >95% at 254 nm. MS:m/z=327 (M+1, ESI+).

General Procedure for Ester Formation from Carboxylic Acid:

To a solution of4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid((C38), 800 mg, 2.96 mmol) in the appropriate alcohol (50 mL) was added4 drops of conc. H₂SO₄. The resulting solution was heated to refluxuntil complete. All organic solvent was evaporated under vacuum. Theresidue was dissolved in EtOAc (30 mL) and washed with sat. NaHCO₃ (30mL). Then the mixture was acidified to pH 3 by adding 1 M HCl. Theorganic layer was dried over MgSO₄, filtered, and evaporated undervacuum. The product was purified using silica gel column chromatography.

19bu 4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoicacid methyl ester (D71)

Using the general procedure for ester formation with MeOH andpurification by silica gel (eluting with 10% EtOAc/hexane) provided 630mg of the title compound in 75% yield. ¹H NMR 400 MHz (DMSO-d₆) δ: 9.22(s, 1H), 7.98 (d, J=9.0 Hz, 2H), 7.78 (d, J=7.8 Hz, 1H), 7.30-7.10 (m,4H), 4.97 (s, 2H), 3.83 (s, 3H); MS (ES) m/z: 285 (M+H)⁺; HPLC purity:96.21% (220 nm), 96.22% (254 nm).

19bv 4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoicacid ethyl ester (D72)

Using the general procedure for ester formation with EtOH andpurification by silica gel (eluting with 10% EtOAc/hexane) provided 350mg the title compound in 39% yield. ¹H NMR 400 MHz (DMSO-d₆) δ: 9.21 (s1H), 7.98 (d, J=9.0 Hz, 2H), 7.78 (d, J=8.2 Hz, 1H), 7.107-7.03 (m, 4H),4.96 (s, 2H), 4.30 (q, J=7.4 Hz, 2H), 1.31 (t, J=7.0 Hz, 3H); MS (ES)m/z: 299 (M+H)⁺; HPLC purity: 97.7% (220 nm), 99.5% (254 nm).

19bw 4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoicacid propyl ester (D73)

Using the general procedure for ester formation with PrOH andpurification by silica gel (eluting with 10% EtOAc/hexane) provided 360mg of the title compound in 39% yield. ¹H NMR 400 MHz (DMSO-d₆) δ: 9.21(s, 1H), 7.99 (d, J=9.0 Hz, 2H), 7.78 (d, J=7.8 Hz, 1H), 7.16-7.05 (m,4H), 4.96 (s, 2H), 4.22 (t, J=6.7 Hz, 2H), 1.76-1.65 (m, 2H), 0.96 (t,7.41 Hz, 3H); MS (ES) m/z: 313 (M+H)⁺; HPLC purity: 96.5% (220 nm),97.6% (254 nm).

19bx 4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoicacid isopropyl ester (D74)

Using the general procedure for ester formation with iPrOH andpurification by silica gel (eluting with 10% EtOAc/hexane) provided 550mg the title compound in 60% yield. ¹H NMR 400 MHz (DMSO-d₆) δ: 9.22 (s,1H), 7.98 (d, 2H), 7.78 (d, 1H), 7.13-7.05 (m, 4H), 5.16-5.08 (m, 1H),4.96 (s, 2H), 1.33 (d, 6H); MS (ES) m/z: 313 (M+H)⁺; HPLC purity: 97.39%(220 nm), 98.23% (254 nm).

19by 4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoicacid 2-dimethylamino-ethyl ester (D75)

To a clear solution of4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid((C38), 0.5 g, 1.75 mmol) in DMF (20 mL) were added N,N-dimethylaminoethanol (0.37 mL, 3.7 mmol) and EDCI (0.71 g, 3.7 mmol). The reactionwas stirred at room temperature overnight. Then DMF was evaporated undervacuum. The residue was purified over silica gel, eluting with 5%MeOH/DCM, to afford the 0.35 g of the title compound in 56% yield. ¹HNMR 400 MHz (DMSO-d₆) δ: 7.97 (d, J=8.9 Hz, 2H), 7.76 (d, J=7.8 Hz, 1H),7.15-7.07 (m, 4H), 4.95 (s, 2H), 4.33 (t, J=5.5 Hz, 2H), 2.58 (t, J=5.9Hz, 2H), 2.20 (s, 6H); MS (ES) m/z: 342 (M+H)⁺; HPLC purity: 91.90% (220nm), 94.99% (254 nm).

Amide Analogues:

General Procedure for Amide Formation from Carboxylic Acid:

To a solution of4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid(C38, 1 g, 3.70 mmol) and the amine (3.70 mmol) were added HATU (1.67 g,4.44 mmol) and DIPEA (1.55 mL, 8.88 mmol) in DMF (20 mL). The reactionwas stirred at room temperature overnight. All organic solvent wasevaporated. The residue was dissolved in EtOAc (50 mL) and washed withwater (3×30 mL). The organic layer was evaporated under vacuum.

19bzN-Benzyl-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide(D76)

Using the general procedure for amide formation with benzyl amine (0.396g, 3.70 mmol) and purification using silica gel column chromatography(25% EtOAc/hexane) afforded 0.8 g of the title compound in 60% yield. ¹HNMR 400 MHz (DMSO-d₆) δ: 9.08 (s, 1H), 9.00 (t, 1H), 7.97 (d, 2H), 7.78(d, 1H), 7.40-7.23 (m, 4H), 7.12-7.02 (m, 4H), 4.97 (s, 2H), 4.48 (d,2H); MS (ES) m/z: 360 (M+H)⁺; HPLC purity: 96.5% (220 nm), 99.4% (254nm).

19ca4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-N-(2-hydroxy-ethyl)-benzamide(D77)

Using the general procedure for amide formation with 2-aminoethanol(0.23 g, 3.70 mmol) and purification by reverse phase chromatography,eluting from 5% MeOH/H₂O to 90% MeOH/H₂O, afforded 0.57 g of the titlecompound in 49% yield. ¹H NMR 400 MHz (DMSO-d₆) δ: 9.16 (s, 1H), 8.38(t, J=5.5 Hz, 1H), 7.90 (d, J=7.0 Hz, 2H), 7.75 (d, J=8.2 Hz, 1H), 7.08(m, 4H), 4.95 (s, 2H), 4.72 (t, J=5.5 Hz, 1H), 3.49 (q, J=6.2 Hz, 2H);MS (ES) m/z: 314 (M+H)⁺; HPLC purity: 94.6% (220 nm), 95.4% (254 nm).

19cb4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-N-pyridin-2-ylmethyl-benzamide(D78)

Using the general procedure for amide formation with 2-aminomethylpyridine (0.4 g, 3.70 mmol) and purification by reverse phasechromatography, eluting from 5% MeOH/H₂O to 90% MeOH/H₂O, afforded 0.55g of the title compound in 41% yield. ¹H NMR 400 MHz (DMSO-d₆) δ: 9.20(s, 1H), 9.10 (t, J=5.8 Hz, 1H), 8.51 (d, J=4.7 Hz, 1H), 7.97 (d, J=8.6Hz, 2H), 7.79-7.73 (m, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.29-7.25 (m, 1H),7.12 (d, J=8.6 Hz, 1H), 7.09-7.03 (m, 1H), 4.95 (s, 2H), 4.56 (d, 6.24Hz, 2H); MS (ES) m/z: 361 (M+H)⁺; HPLC purity: 98.4% (220 nm), 99.5%(254 nm).

19cc[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-(4-methyl-piperazin-1-yl)-methanone(D79)

Using the general procedure for amide formation with 1-methylpiperazine(0.41 g, 3.70 mmol) and purification by reverse phase chromatography,eluting from 5% MeOH/H₂O to 90% MeOH/H₂O, afforded 0.23 g of the titlecompound in 18% yield. ¹H NMR 400 MHz (DMSO-d₆) δ: 9.20 (s, 1H), 7.78(d, 1H), 7.42 (d, 2H), 7.14-7.06 (m, 4H), 4.96 (s, 2H), 3.58 (br, 4H),2.32 (br, 4H), 2.20 (s, 3H); MS (ES) m/z: 353 (M+H)⁺; HPLC purity:96.24% (220 nm), 97.00% (254 nm).

19cd1-{4-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoyl]-piperazin-1-yl}-ethanone(D80)

Using the general procedure for amide formation with 1-acetylpiperazine(0.474 g, 3.70 mmol) and purification by reverse phase chromatography,eluting from 5% MeOH/H₂O to 90% MeOH/H₂O, afforded 0.98 g of the titlecompound in 70% yield. ¹H NMR 400 MHz (DMSO-d₆) δ: 9.19 (s, 1H), 7.75(d, J=7.8 Hz, 1H), 7.47 (d, J=7.3 Hz, 2H), 7.12-7.02 (m, 4H), 4.96 (s,2H), 2.02 (s, 3H), 3.46 (br, 8H); MS (ES) m/z: 381 (M+H)⁺; HPLC purity:97.17% (220 nm), 99.67% (254 nm).

19ceN-(2-Dimethylamino-ethyl)-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide(D81)

Using the general procedure for amide formation with2-amino-1-dimethylaminoethane (0.4 g, 3.70 mmol) and purification byreverse phase chromatography, eluting from 5% MeOH/H₂O to 90% MeOH/H₂O,afforded 0.55 g of the title compound in 41% yield. ¹H NMR 400 MHz(DMSO-d₆) δ: 9.21 (s, 1H), 8.65 (t, 1H), 7.92 (d, 2H), 7.78 (d, 1H),7.16 (d, 2H), 7.06-7.01 (m, 2H), 4.98 (s, 2H), 3.59 (q, 2H), 3.26-3.20(m, 2H), 2.82 (s, 6H); MS (ES) m/z: 341 (M+H)⁺; HPLC purity: 96.13% (220nm), 98.38% (254 nm).

19cj6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinonitrile(D82)

To a solution of 6-chloro-nicotinonitrile (3.5 g, 25.0 mmol, 1.0 eq.),2-bromo-5-hydroxy-benzaldehyde (5.0 g, 25.0 mmol, 1.0 eq.) in DMF (40.0mL) was added K₂CO₃ (4.1 g, 30.0 mmol, 1.2 eq.) under nitrogenatmosphere. The mixture was heated at 80° C. overnight. After cooling toroom temperature, the mixture was poured into EtOAc (30 mL) and H₂O (30mL). The layers were separated and the aqueous phase was extracted withEtOAc (3×20 mL). Combined organic extracts was washed with brine (30mL), dried over MgSO₄, filtered and the filtrate was concentrated underreduced pressure. The residue was applied to silica chromatographyeluting with MeOH/DCM (0:100 to 10:90) to give6-(4-bromo-3-formyl-phenoxy)-nicotinonitrile as a white solid. ¹H NMR(CHLOROFORM-d) δ: 10.35 (s, 1H), 8.43 (dd, J=2.3, 0.6 Hz, 1H), 7.98 (dd,J=8.6, 2.3 Hz, 1H), 7.69-7.77 (m, 2H), 7.30 (dd, J=8.6, 3.0 Hz, 1H),7.12 (dd, J=8.6, 0.8 Hz, 1H). Amount obtained, 5.92 g, 78% yield.

To a solution of 6-(4-bromo-3-formyl-phenoxy)-nicotinonitrile (4.16 g,13.7 mmol, 1.0 eq.) in 1,4-dioxane (120 mL) was addedbis-pinacol-diboron (3.83 g, 15.1 mmol, 1.1 eq.), KOAc (4.03 g, 41.1mmol, 3.0 eq.) and PdCl₂(dppf)₂ (300 mg, 0.4 mmol, 0.03 eq.). Themixture was degassed with N₂ and heated at 80° C. overnight. Aftercooling to room temperature, the mixture was filtered though a shortpack of celite and the filtrate was concentrated under reduced pressure.The residue was applied to silica chromatography eluting withEtOAc/Heptanes (0:100 to 70:30) to give6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrileas a yellow solid. ¹H NMR (CHLOROFORM-d) δ: 10.67-10.69 (m, 1H),8.42-8.45 (m, 1H), 8.01-8.05 (m, 1H), 7.94-7.98 (m, 1H), 7.74-7.77 (m,1H), 7.36-7.41 (m, 1H), 7.07-7.11 (m, 1H), 1.38-1.40 (m, 12H). Amountobtained, 4.1 g, 85.4% yield.

To a suspension of6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(1.67 g, 4.8 mmol, 1.0 eq.) in EtOH (30 mL) at 0° C. was added NaBH₄(180.4 mg, 4.76 mmol, 1.0 eq.) in small portions. The mixture wasstirred at 0° C. for 20 minutes and allowed to warm to room temperaturein another 1 h. After cooling to 0° C., the clear solution was carefullytreated with H₂O (1 mL), followed by slow addition of HCl (10 mL, 3N).The resulting yellow suspension was allowed to ward to room temperaturegradually and stirred for 2 h. The mixture was then treated with sat.NaHCO₃ drop wise until PH reaching 7. The precipitate was collected byfiltration, washed with H₂O to give6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrileas a white solid. LCMS (m/z) 253 (M+H); ¹H NMR (DMSO-d₆) δ: 9.19 (s,1H), 8.60-8.66 (m, 1H), 8.31 (dd, J=8.7, 2.4 Hz, 1H), 7.76 (d, J=8.0 Hz,1H), 7.20-7.28 (m, 2H), 7.13 (dd, J=8.0, 2.0 Hz, 1H), 4.96 (s, 2H).Amount obtained, 1.1 g, 92.4% yield.

19ck 4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoicacid butyl ester (D83)

Using the general procedure for ester formation with BuOH andpurification by silica gel.

19cl3-fluoro-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile(D84)

This compound was obtained in a similar manner to Example 19b (D2) from3,4-difluorobenzonitrile and 4-bromo-3-(1,3-dioxolan-2-yl)phenol.

19cm3-ethyl-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile(D85)

This compound was obtained in a similar manner to Example 19b (D2) from4-fluoro-3-methylbenzonitrile and 4-bromo-3-(1,3-dioxolan-2-yl)phenol.

19cn4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-(2-methoxyethoxy)-benzonitrile(D86)

This compound was prepared in a similar manner to Example 19at (D46)using 2-methoxyethanol and sodium hydride instead of sodium methoxide.

¹H NMR 400 MHz (d₆-DMSO) δ3.22 (s, 3H), 3.53 (t, J=4.7 Hz, 2H), 4.24 (t,J=4.7 Hz, 2H), 4.99 (s, 2H), 6.71 (d, J=8.2 Hz, 1H), 7.21 (d, J=7.8 Hz,1H), 7.30 (s, 1H), 7.79 (d, J=8.2 Hz, 1H), 8.25 (d, J=8.6 Hz, 1H), 9.26(s, 1H). Mass Spectrum [M+H⁺]=327.

19co 5-(4-Fluorophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (D87)

To a solution of A (7.22 g) and K₂CO₃ (17.8 g) in DMF (200 ml) was added5-fluoro-2-nitrotoluene (10 g) under Ar. The reaction mixture wasstirred at 80° C. overnight and filtrated, extracted with ether. Theorganic layer was separated, dried (Na₂SO₄), filtered, and the solventwas evaporated to give compound B (16 g; 99%). LC-MS: 248 (M+H)⁺.

To the solution of B (16 g) in EtOAc (200 ml) was added Pd/C (2 g). Thereaction mixture was stirred at room temperature under H₂ overnight andfiltrated, and the solvent was evaporated to obtained compound C (13 g;99%). LC-MS: 218 (M+H)⁺.

To a solution of CuBr₂ (16 g) in MeCN (140 ml) was added t-BuONO (10 ml)at −10° C. After 0.5 h, to the reaction mixture was added C (16 g) inMeCN (10 ml). The reaction mixture was stirred at −10° C. overnight andfiltrated, the solvent was evaporated and the residue was purified bychromatography to give D (2.4 g; 15%). GC-MS: 281.

To a solution of D (2.4 g) and NBS (1.6 g) in CCl₄ (25 ml) was addedbenzoyl peroxide (200 mg). The reaction mixture was stirred at 70° C.overnight, filtrated, and washed with water. The organic layer was dried(Na₂SO₄), filtered, and the solvent was evaporated to give compound E(2.7 g; 99%)

To a solution of E (2.7 g) in DMF (50 ml) was added NaOAc (4 g). Thereaction mixture was stirred at 70° C. for 5 h, filtrated, and extractedwith ether. The organic layer was separated, dried (Na₂SO₄), filtered,and the solvent was evaporated to give compound F (2 g; 99%).

To a solution of F (2 g) in THF (20 ml) was added NaOH/H₂O (10%; 20 ml).The reaction mixture was stirred at room temperature overnight, HCl/H₂O(4 M) was added to ca. pH 7, and the mixture was extracted with EtOAc.The organic layer was dried (Na₂SO₄), filtered, and the solvent wasevaporated to give G (1.5 g; 88%). LC-MS: 297 (M+H)⁺.

To a solution of G (1.5 g) and DIPEA (0.97 g) in DCM (20 ml) was added(chloromethoxy)ethane (0.7 g). The reaction mixture was stirred at roomtemperature overnight and was evaporated. Purification of the residue bychromatography gave compound H (1 g; 58%). LC-MS: 356 (M+H)⁺.

To the solution of H (1 g), KOAc (0.8 g) and PdCl₂ (dppf) (0.12 g) indioxane (5 ml) was added bis(pinacolato)diboron (1 g) under Ar. Thereaction mixture was stirred at 70° C. overnight, washed with water,extracted with DCM, and the organic layer was evaporated. The residuewas purified by HPLC to give compound I (800 mg; 70%).

To a solution of I (800 mg) in THF (20 ml) was added HCl/H₂O (6M; 20ml). The reaction mixture was stirred at room temperature overnight andextracted with DCM. The organic layer was dried and evaporated. Theresidue was purified by HPLC to give the desired compound (300 mg; 60%).LC-MS: 245 (M+H)⁺.

19 cp 5-(4-Chlorophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (D88)

To a solution of A (18 g) and K₂CO₃ (36 g) in DMF (200 ml) was added5-fluoro-2-nitrotoluene (20 g) under Ar. The reaction mixture wasstirred at 70° C. overnight, filtrated, diluted with water and extractedwith ether. The organic layer was separated, dried (Na₂SO₄), filtered,and the solvent was evaporated to obtained compound B (36 g; 99%).LC-MS: 264 (M+H)

To a solution of B (36 g) in HCl (150 ml) was added SnCl₂ (116 g). Thereaction mixture was stirred at room temperature for 1 h. filtered,extracted with EtOAc and the solvent was evaporated to obtained compoundC (30 g; 97%). LC-MS: 234 (M+H)⁺.

To a solution of CuBr₂ (42 g) in MeCN (500 ml) was added t-BuONO (22 ml)at −10° C. After 0.5 h, to the reaction mixture was addedANA-PO4209-3A-3 (30 g) in MeCN (10 ml). The reaction mixture was stirredat −10 overnight, filtered, and the solvent was evaporated. The residuewas purified by chromatography to give compound ANA-PO4209-3A-4 (8.4 g;22%). GC-MS: 297.

To a solution of D (8.4 g) and NBS (5.5 g) in CCl₄ (200 ml) was addedbenzoyl peroxide (800 mg). The reaction mixture was stirred at 70° C.overnight, filtered, and washed with water. The organic layer was dried(Na₂SO₄), filtered, and the solvent was evaporated to give compound E(10 g; 99%)

a solution of E; (10 g) in DMF (250 ml) was added NaOAc (15 g). Thereaction mixture was stirred at 70° C. for 5 h, filtrated, diluted withwater and extracted with ether. The organic layer was separated, dried(Na₂SO₄), filtered, and the solvent was evaporated to give compound F(9.6 g; 99%).

To a solution of F (9.6 g) in THF (50 ml) was added NaOH/H₂O (10%; 50ml). The reaction mixture was stirred at room temperature overnight,HCl/H₂O (4 M) was added to ca. pH7, and the whole was extracted withEtOAc. The organic layer was dried (Na₂SO₄), filtered, and the solventwas evaporated to give compound G (7.5 g; 89%). LC-MS: 313 (M+H)⁺.

To a solution of G (7.5 g) and DIPEA (3.87 g) in DCM (200 ml) was added(chloromethoxy)ethane (2.9 g). The reaction mixture was stirred at roomtemperature overnight and was evaporated purified by chromatography togive compound H (9 g; 99%). LC-MS: 372 (M+H)⁺.

To a solution of H (9 g), KOAc (7 g) and PdCl₂(dppf) (0.98 g) in dioxane(100 ml) was added bis(pinacolato)diboron (9.1 g) under Ar. The reactionmixture was stirred at 70° C. overnight, diluted with water, extractedwith DCM, and the organic layer was evaporated and purified by HPLC togive compound I (8 g; 80%).

To a solution of I (8 g) in THF (80 ml) was added HCl/H₂O (6 M; 80 ml).The reaction mixture was stirred at room temperature overnight,extracted with DCM, and evaporated. The residue was purified by HPLC togive the desired compound (2 g; 40%). LC-MS: 261 (M+H)⁺.

19cq 5-(4-Methylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (D89)

Compound A (8 g, 58.8 mmol), compound B (8 g, 39.8 mmol), Cu(OAc)₂ (8.4g, 47.8 mmol) and 4 A MS (11 g) were suspended in dry DCM (100 mL), Et₃N(11.2 mL) and pyridine (33.6 mL) were added, and the reaction wasstirred at room temperature under Ar for 48 h, filtered and washed by 1M HCl, the organic layer was combined and dried over MgSO₄. The crudewas purification by chromatography using 20:1 PE/EA to give compound C(4.2 g, 30%). GC-MS 290 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃) δ 10.299 (s, 1H),7.589 (d, J=8.8 Hz, 1H), 7.458 (d, J=2.8 Hz, 1H), 7.195 (d, J=8.0 Hz,2H), 7.107 (dd, J=2.8 Hz, J=8.4 Hz, 1H), 6.936 (d, J=8.4 Hz, 2H), 2.366(s, 1H).

A mixture of compound C (5 g, 17.2 mmol) and NaBH₄ (320 mg, 8.6 mmol) inMeOH (50 mL) was stirred for 1 h at ambient temperature and evaporated.The residue was purification by chromatography using 6:1 PE/EA to givecompound D (5 g, 100%). GC-MS 292 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃) δ 7.465(d, J=8.0 Hz, 1H), 7.272 (d, J=8.0 Hz, 2H), 7.171-7.133 (m, 1H), 6.931(d, J=8.4 Hz, 2H), 6.811 (d, J=8.0 Hz, 1H), 4.701 (s, 2H), 2.351 (s,3H).

A mixture of compound D (1.6 g, 5.5 mmol) and NaH (217 mg, 9.0 mmol) inDMF (20 mL) was stirred for 30 min at 0° C. EOM-Cl (800 mg, 8.5 mmol)was added, and the mixture was stirred for 1 h at ambient temperatureand evaporated. The residue was purification by chromatography using10:1 PE/EA to give compound E (1.6 g, 84%). ¹HNMR (400 MHz, CDCl₃) δ7.470 (d, J=9.2 Hz, 1H), 7.168-7.146 (m, 3H), 6.929 (d, J=8.4 Hz, 2H),6.811 (d, J=9.2 Hz, 1H), 4.803 (s, 2H), 4.636 (s, 2H), 3.661-3.645 (m,2H), 2.352 (s, 3H), 1.255-1.220 (m, 3H).

A mixture of compound E (1.6 g, 4.6 mmol), bis(pinacolato)diboron (1.7g, 7.1 mmol), PdCl₂(dppf) (98 mg) and KOAc (1.3 g, 13.2 mmol) in1,4-dioxane (20 mL) was stirred overnight at 80° C. under Ar. Thesolvent was evaporated. The residue was purification by chromatographyusing 10:1 PE/EA to give compound F (1.6 g, 89%). ¹HNMR (400 MHz, CDCl₃)δ 7.778 (d, J=8.0 Hz, 1H), 7.159 (d, J=8.8 Hz, 2H), 6.942 (d, J=8.0 Hz,2H), 6.856 (m, 1H), 4.854 (s, 2H), 4.797 (s, 2H), 3.659-3.606 (m, 2H),2.349 (s, 3H), 1.333 (s, 12H), 1.240-1.206 (m, 3H).

A mixture of compound F (1.6 g, 4.0 mmol) in 6 M HCl (8 mL) and THF (8mL) was stirred overnight at ambient temperature and evaporated. Theresidue was purification by prepared-HPLC to give the desired compound(600 mg, 63%). LC-MS 241 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃) δ 7.684 (d,J=8.4 Hz, 1H), 7.197 (d, J=7.6 Hz, 2H), 7.007-6.956 (m, 3H), 6.875 (s,1H), 5.026 (s, 2H), 2.368 (s, 3H).

19cr 5-(4-Trifluoromethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (D90)

To a solution of A (10.1 g, 53.3 mmol), 2-bromo-5-hydroxybenzaldehyde(6.7 g, 33.3 mmol), 4 A MS (25 g) and Cu(OAc)₂ (7.84 g, 43.3 mmol) indry CH₂Cl₂ (150 ml) was added pyridine (4.74 g, 59.9 mmol) and Et₃N (8.4ml, 59.9 mmol) under Ar. The reaction mixture was stirred at ambienttemperature overnight and filtrated, washed with 2N HCl, extracted withCH₂Cl₂. The organic layer was separated, dried (Na₂SO₄), filtered, andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: petroleum ether/EtOAc 25/1). Thepure fractions were collected, and the solvent was evaporated to affordB (3.49 g, 30%): ¹H NMR (CDCl₃) δ 7.07 (2H, d, J=8.8 Hz), 7.18 (1H, dd,J=2.8, 8.4 Hz), 7.55 (1H, d, J=2.8 Hz), 7.61-7.67 (3H, m), 10.32 (1H,s).

To a solution of B (3.49 g, 10.1 mmol) in MeOH (40 ml) was added NaBH₄(192 mg, 5.06 mmol). The reaction mixture was stirred at ambienttemperature for 0.5 h. The solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: petroleumether/EtOAc 15/1). The pure fraction was collected, and the solvent wasevaporated to afford C (3.25 g, 93%): ¹H NMR (CDCl₃) δ 1.79 (1H, s),4.73 (2H, s), 6.87 (1H, dd, J=2.4, 8.8 Hz), 7.05 (2H, d, J=8.4 Hz), 7.23(1H, d, J=2 Hz), 7.53 (1H, d, J=9.2 Hz), 7.59 (2H, d, J=8.8 Hz).

To a solution of C (3.7 g, 10.6 mmol) in dry DMF (20 ml) was added NaH(462 mg, 10.6 mmol, 55%) under Ar. The reaction mixture was stirred at0° C. for 0.5 h, then (chloromethoxy)ethane (1.3 g, 13.8 mmol) wasadded. The reaction mixture was stirred at ambient temperature for 1 hand quenched with i-PrOH. The solvent was evaporated under high vacuum.The residue was dissolved in EtOAc, washed with water. The organic layerwas separated, dried (Na₂SO₄), filtered, and the solvent was evaporated.The residue was purified by column chromatography over silica gel(eluent: petroleum ether/EtOAc 100/1). The pure fractions werecollected, and the solvent was evaporated to afford D (3.1 g, 76%): ¹HNMR (CDCl₃) δ 1.22 (3H, t, J=6.8 Hz), 3.61-3.66 (2H, m), 4.64 (2H, s),4.80 (2H, s), 6.85 (1H, dd, J=2.8, 8.8 Hz), 7.04 (2H, d, J=8.8 Hz), 7.23(1H, d, J=2.8 Hz), 7.53 (1H, d, J=8.8 Hz), 7.58 (2H, d, J=9.2 Hz).

A mixture of D (3.1 g, 7.7 mmol), bis(pinacolato)diboron (5.87 g, 23.1mmol), PdCl₂(dppf)₂ (186 mg, 0.23 mmol) and KOAc (2.26 g, 23.1 mmol) in1,4-dioxane (40 mL) was stirred at 80° C. overnight under Ar. Theorganic layer was removed. The residue was purified by columnchromatography over silica gel (eluent: petroleum ether). The purefractions were collected, and the solvent was evaporated to afford E(2.6 g, 75%): ¹H NMR (CDCl₃) δ 1.21 (3H, t, J=6.8 Hz), 1.33 (12H, s),3.59-3.64 (2H, m), 4.79 (2H, s), 4.86 (2H, s), 6.92 (1H, dd, J=2.8, 7.6Hz), 7.05 (2H, d, J=8.4 Hz), 7.19 (1H, d, J=1.6 Hz), 7.56 (2H, d, J=8.0Hz), 7.83 (1H, d, J=7.6 Hz).

A mixture of E (2.6 g, 5.75 mmol) in 6 M HCl (26 mL) and THF (26 mL) wasstirred at ambient temperature overnight. The solvents were removed. Theresidue was purification by preparative HPLC to obtain the desiredcompound (370 mg, 22%): ¹H NMR (DMSO-d₆) δ 4.96 (2H, s), 7.08 (1H, m),7.13 (1H, s), 7.20 (2H, d, J=8.5 Hz), 7.77 (3H, m), 9.21 (1H, s).

19cs5-(4-(4-methylpiperazin-1-ylsulfonyl)phenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (D91)

To a solution of 2-bromo-5-hydroxybenzaldehyde (14 g) andp-toluenesulfonic acid (1.4 g) in toluene (400 ml) was addedethane-1,2-diol (6.5 g). The reaction mixture was heated underDean-stark conditions overnight and cool to room temperature. Thereaction mixture was evaporated under reduced pressure, dissolved inDCM, filtered, and the solvent was evaporated to give compound A (15 g;88%). LC-MS: 246 (M+H)⁺.

To a solution of 1-methylpiperazine (5.5 g) in DCM (200 ml) was addedEt₃N (10.5 g) at 0° C. After stirring 0.5 h, to the reaction mixture wasadded 4-fluorobenzene-1-sulfonyl (10 g) dropwise. The reaction mixturewas stirred at 0° C. for 2 h, then was stirred at room temperatureovernight and washed with water. The organic layer was dried (Na₂SO₄),filtered, and the solvent was evaporated to give compound B (13 g; 97%).LC-MS: 259 (M+H)⁺.

To a solution of B (8 g) and K₂CO₃ (8.3 g) in DMF (250 ml) was added A(8.3 g) under Ar. The reaction mixture was stirred at 150° C. for 3 hfiltrated, diluted with ether and washed with water. The organic layerwas separated, dried (Na₂SO₄), filtered, and the solvent was evaporatedto obtained compound C (14 g; 96%). LC-MS: 484 (M+H)⁺.

To a solution of C (14 g) in THF (100 ml) was added HCl (12 M; 100 ml).The reaction mixture was stirred at room temperature overnight andextracted with DCM. The organic layer was separated, dried (Na₂SO₄),filtered, and the solvent was evaporated to give compound D (12 g; 94%).LC-MS: 440 (M+H)⁺.

To the solution of D (12 g), KOAc (7.9 g) and PdCl₂(dppf) (1.1 g) indioxane (80 ml) was added bis(pinacolato)diboron (10.4 g) under Ar. Thereaction mixture was stirred at 70° C. overnight, diluted with water,and extracted with DCM. The organic layer was separated, dried (Na₂SO₄),filtered, and the solvent was evaporated to give compound E (5 g; 37%)

To a solution of E (5 g) in THF (40 ml) was added NaBH₄ (1 g). Thereaction mixture was stirred at room temperature overnight, HCl/H₂O (4M) was added, and the whole extracted with EtOAc. The organic layer wasseparated, dried (Na₂SO₄), filtered, and the solvent was evaporated togive compound F (800 mg; 16%). LC-MS: 489 (M+H)⁺.

To a solution of F (800 mg) in THF (20 ml) was added HCl/H₂O (6 M; 20ml). The reaction mixture was stirred at room temperature overnight andextracted with DCM. The organic layer was evaporated and the residue waspurified by HPLC to give the desired compound (100 mg; 16%). LC-MS: 389(M+H)⁺.

19ctN,N-diethyl-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzenesulfonamide(D92)

To a solution of 2-bromo-5-hydroxybenzaldehyde (5 g) and toluenesulfonicacid (0.13 g) in toluene (200 ml) was added ethane-1,2-diol (3.8 g). Thereaction mixture was heated under Dean-stark conditions overnight andcool to room temperature. The reaction mixture was evaporated underreduced pressure, DCM was added, the mixture filtered, and the solventwas evaporated to give compound A (5 g; 83%). LC-MS: 246 (M+H)⁺.

To a solution of diethylamine (1 g) in DCM (50 ml) was added Et₃N (2.8g) at 0° C. After stirring 0.5 h, to the reaction mixture was added4-fluorobenzene-1-sulfonyl (2.9 g) dropwise. The reaction mixture wasstirred at 0° C. for 2 h, then was stirred at room temperature overnightand washed with water. The organic layer was dried (Na₂SO₄), filtered,and the solvent was evaporated to give compound B (2.5 g; 78%). LC-MS:232 (M+H)⁺.

To a solution of B (2.5 g) and K₂CO₃ (2.7 g) in DMF (100 ml) was added A(2.5 g) under Ar₂. The reaction mixture was stirred at 150° C. for 3 h,filtered, and extracted with ether. The organic layer was separated,dried (Na₂SO₄), filtered, and the solvent was evaporated to givecompound C (5 g; 100%). LC-MS: 458 (M+H)⁺.

To a solution of C (5 g) in THF (40 ml) was added HCl (12 M; 40 ml). Thereaction mixture was stirred at room temperature overnight and extractedwith DCM. The organic layer was separated, dried (Na₂SO₄), filtered, andthe solvent was evaporated to give compound D (4.1 g; 100%). LC-MS: 414(M+H)⁺.

To the solution of D (4.1 g), KOAc (2.9 g) and PdCl₂(dppf) (0.4 g) indioxane (80 ml) was added bis(pinacolato)diboron (3.8 g) under Ar. Thereaction mixture was stirred at 70° C. overnight diluted with water, andextracted with DCM. The organic layer was separated, dried (Na₂SO₄),filtered, and the solvent was evaporated to give compound E (3 g; 66%)

To a solution of E (3 g) in THF (40 ml) was added NaBH₄ (1 g). Thereaction mixture was stirred at room temperature overnight and addedHCl/H₂O (4 M), extracted with EtOAc. The organic layer was separated,dried (Na₂SO₄), filtered, and the solvent was evaporated to obtainedcompound F (1.3 g; 43%). LC-MS: 462 (M+H)⁺.

To a solution of F (1.3 g) in THF (30 ml) was added HCl/H₂O (6 M; 30ml). The reaction mixture was stirred at room temperature overnight,extracted with DCM, evaporated and purified by HPLC to obtained thedesired compound (300 mg; 30%). LC-MS: 362 (M+H)⁺.

19cu 5-(4-methoxyphenoxy)benzo[c][1,2]oxaborol-1 (3H)-ol (D93)

Preparation of B

A (11 g, 5.97 mol), 2-bromo-5-hydroxybenzaldehyde (9 g, 45 mmol),Cu(OAc)₂ (9.8 g, 54 mmol) and 4 A MS (20 g) were suspended in dry DCM(100 mL), Et₃N (12.6 mL) and pyridine (37.8 mL) were added, and thereaction was stirred at room temperature under Ar for 48 h. The mixturewas filtered and extracted by 1 M HCl. The organic layer was combinedand dried over MgSO₄. The crude was purification by chromatography using20:1 PE/EA to give compound B (2.2 g, 15%). GC-MS 308 (M+H)⁺.

Preparation of C

A mixture of B (80 mg, 0.26 mmol) and NaBH₄ (5 mg, 0.13 mmol) in MeOH (3mL) was stirred for 1 h at ambient temperature. The solvent was removed.The residue was purified by chromatography using 6:1 PE/EA to give C (70mg, 88%). ¹HNMR (400 MHz, CDCl₃) δ 7.447 (d, J=8.4 Hz, 1H), 7.100 (d,J=2.1 Hz, 1H), 6.993 (d, J=9.2 Hz, 2H), 6.909 (d, J=9.2 Hz, 2H), 6.768(dd, J=2.4 Hz, J=8.0 Hz, 1H), 4.688 (s, 2H), 3.820 (s, 3H).

Preparation of D

A mixture of C (1.45 g, 4.7 mmol) and NaH (187 mg, 7.8 mmol) in DMF (20mL) was stirred for 30 min at 0° C. EOM-Cl (689 mg, 7.3 mmol) was added,and the mixture was stirred for 1 h at ambient temperature. The solventwas removed. The residue was purified by chromatography using 10:1 PE/EAto give D (1.4 g, 82%). ¹HNMR (400 MHz, CDCl₃) δ 7.449 (d, J=9.2 Hz,1H), 7.128 (d, J=3.6 Hz, 1H), 6.987 (d, J=8.4 Hz, 2H), 6.904 (d, J=9.6Hz, 1H), 6.747 (dd, J=3.2 Hz, J=8.4 Hz, 1H), 4.797 (s, 2H), 4.622 (s,2H), 3.819 (s, 3H), 3.674-3.622 (m, 2H), 1.251-1.215 (m, 3H).

Preparation of E

A mixture of D (700 mg, 1.9 mmol), bis(pinacolato)diboron (741 mg, 3.0mmol), PdCl₂(dppf) (42 mg) and KOAc (570 mg, 5.5 mmol) in 1,4-dioxane(10 mL) was stirred overnight at 80° C. under Ar. The solvent wasremoved. The residue was purification by chromatography using 10:1 PE/EAto give E (700 mg, 89%). ¹HNMR (400 MHz, CDCl₃) δ 7.767 (d, J=8.4 Hz,1H), 7.092 (s, 1H), 7.001 (d, J=8.8 Hz, 2H), 6.903 (d, J=9.2 Hz, 2H),6.814 (dd, J=1.6 Hz, J=8.0 Hz, 1H), 4.840 (s, 2H), 4.795 (s, 2H),3.659-3.606 (m, 2H), 3.819 (s, 3H), 3.659-3.607 (m, 2H), 1.330 (s, 12H),1.242-1.207 (m, 3H).

Preparation of (D93)

A mixture of E (700 mg, 1.7 mmol) in 6 M HCl (4 mL) and THF (4 mL) wasstirred overnight at ambient temperature. The solvents were removed. Theresidue was purified by preparative-HPLC to give the desired compound(300 mg, 69%). LC-MS 257 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃) δ 7.665 (d,J=8.0 Hz, 1H), 7.026 (d, J=9.2 Hz, 2H), 6.976 (dd, J=2.0 Hz, J=8.0 Hz,1H), 6.926 (d, J=9.2 Hz, 2H), 6.826 (d, J=1.6 Hz, 1H), 5.014 (s, 2H),3.823 (s, 3H).

19cv 5-(3,4-dimethoxyphenoxy)benzo[c][1,2]oxaborol-1 (3H)-ol (D94)

Preparation of B

To a solution of A (14.6 g, 80.2 mmol), 2-bromo-5-hydroxybenzaldehyde(10.08 g, 50.2 mmol), 4 A MS (30 g) and Cu(OAc)₂ (10.88 g, 60.2 mmol) indry CH₂Cl₂ (200 ml) was added pyridine (7.12 g, 90.2 mmol) and Et₃N(12.7 ml, 90.2 mmol) under Ar. The reaction mixture was stirred atambient temperature overnight and filtrated, washed with 2N HCl, andextracted with CH₂Cl₂. The organic layer was combined, dried (Na₂SO₄),filtered, and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: petroleum ether/EtOAc15/1). The pure fraction was collected, and the solvent was evaporatedto afford B (1.84 g, 11%): ¹H NMR (CDCl₃) δ 3.84 (3H, s), 3.89 (3H, s),6.56-6.62 (2H, m), 6.84 (1H, d, J=8.8 Hz), 7.10 (1H, dd, J=2.8, 8.4 Hz),7.43 (1H, d, J=2.8 Hz), 7.56 (1H, d, J=9.2 Hz), 10.29 (1H, s).

Preparation of Compound C

To a solution of B (2.16 g, 6.42 mmol) in MeOH (150 ml) was added NaBH₄(120 mg, 3.15 mmol). The reaction mixture was stirred at ambienttemperature for 0.5 h. The solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: petroleumether/EtOAc 3/1). The pure fractions were collected, and the solvent wasevaporated to afford C (2.2 g, 99%): ¹H NMR (CDCl₃) δ 1.57 (1H, s), 3.83(3H, s), 3.87 (3H, s), 4.69 (2H, d, J=6.0 Hz), 6.56 (1H, dd, J=2.4, 8.8Hz), 6.62 (1H, d, J=2.4 Hz), 6.76 (1H, dd, J=2.4, 8.8 Hz), 6.82 (1H, d,J=9.2 Hz), 7.11 (1H, d, J=2.4 Hz), 7.43 (1H, d, J=8.4 Hz).

Preparation of D

To a solution of C (2.2 g, 6.4 mmol) in dry DMF (25 ml) was added NaH(279 mg, 6.4 mmol, 55%) under Ar. The reaction mixture was stirred at 0°C. for 0.5 h, then (chloromethoxy)ethane (782 mg, 8.32 mmol) was added.The reaction mixture was stirred at ambient temperature for 1 h andquenched with i-PrOH. The solvent was evaporated under high vacuum. Theresidue was dissolved in EtOAc, washed with water. The organic layer wasseparated, dried (Na₂SO₄), filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:petroleum ether/EtOAc 10/1). The pure fraction was collected, and thesolvent was evaporated to afford D (1.8 g, 71%): ¹H NMR (CDCl₃) δ 1.22(3H, t, J=8.0 Hz), 3.61-3.66 (2H, m), 3.83 (3H, s), 3.88 (3H, s), 4.61(2H, s), 4.79 (2H, s), 6.55 (1H, dd, J=2.8, 8.4 Hz), 6.62 (1H, d, J=2.0Hz), 6.74 (1H, dd, J=2.4, 9.2 Hz), 6.82 (1H, d, J=8.4 Hz), 7.12 (1H, d,J=2.4 Hz), 7.44 (1H, d, J=8.4 Hz).

Preparation of E

A mixture of D (1.8 g, 4.53 mmol), bis(pinacolato)diboron (3.45 g, 13.6mmol), PdCl₂(dppf)₂ (109 mg, 0.13 mmol) and KOAc (1.33 g, 13.6 mmol) in1,4-dioxane (20 mL) was stirred at 80° C. overnight under Ar. Theorganic layer was removed. The residue was purified by columnchromatography over silica gel (eluent: petroleum ether/EtOAc 15/1). Thepure fractions were collected, and the solvent was evaporated to affordE (1.84 g, 82%): ¹H NMR (CDCl₃) δ 1.21 (3H, t, J=6.8 Hz), 1.32 (12H, s),3.60-3.65 (2H, m), 3.81 (3H, s), 3.88 (3H, s), 4.79 (2H, s), 4.83 (2H,s), 6.59 (1H, dd, J=2.4, 8.4 Hz), 6.64 (1H, d, J=2.8 Hz), 6.80-6.83 (2H,m), 7.10 (1H, d, J=2.0 Hz), 7.75 (1H, d, J=8.4 Hz).

Preparation of (D94)

A mixture of E (1.84 g, 4.14 mmol) in 6 M HCl (40 mL) and THF (60 mL)was stirred at ambient temperature overnight. The solvents were removed.The residue was purification by preparative HPLC to give the desiredcompound (615 mg, 52%): ¹H NMR (DMSO-d₆) δ 3.73 (3H, s), 3.76 (3H, s),4.91 (2H, s), 6.59 (1H, dd, J=2.5, 9.0 Hz), 6.77 (1H, d, J=2.5 Hz), 6.89(1H, s), 6.94 (1H, dd, J=1.5, 8.0 Hz), 6.97 (1H, d, J=8.5 Hz), 7.69 (1H,d, J=8.0 Hz), 9.11 (1H, s).

19cw2-Dimethylamino-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D95)

D95 6-(4-Bromo-3-formyl-phenoxy)-2-chloro-nicotinonitrile (3)

Triethylamine (11.0 mL, 78.0 mmol) was added to a solution of2-bromo-5-hydroxy-benzaldehyde (1) (7.84 g, 39.0 mmol) and2,6-dichloro-nicotinonitrile (2) (7.42 g, 42.9 mmol) in a sealablereaction vessel. The reaction vessel was sealed with a teflon cap andheated at 70° C. for 18 hr. The reaction was left to cool to roomtemperature and concentrated to give an orange oil (18.0 g). The oil wasdiluted with CH₂Cl₂ (200 mL) followed by the addition of silica gel (70g, 230-400 mesh) and concentrated to dryness. This was loaded onto asilica gel column (70 g, 230-400 mesh) and eluted with gradient 5-40%EtOAc/hexanes. Isolated a mixture of6-(4-bromo-3-formyl-phenoxy)-2-chloro-nicotinonitrile (3) and2-(4-bromo-3-formyl-phenoxy)-6-chloro-nicotinonitrile (4) in a ratio of2:1, respectively (5.80 g) as a clear oil which later solidified to awhite solid. The mixture was carried forward with further purification.

6-(4-bromo-3-formyl-phenoxy)-2-chloro-nicotinonitrile (3) ¹H NMR 400 MHz(CDCl₃) δ10.35 (s, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H),7.69 (d, J=2.7 Hz, 1H), 7.30 ppm (dd, J=8.6, 2.7 Hz, 1H), 7.02 (d, J=8.6Hz, 1H).

2-(4-bromo-3-formyl-phenoxy)-6-chloro-nicotinonitrile (4) ¹H NMR 400 MHz(CDCl₃) δ10.35 (s, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H),7.73 (d, J=2.3 Hz, 1H), 7.34 (dd, J=7.8, 2.3 Hz, 1H), 7.17 (d, J=7.8 Hz,1H).

6-(4-Bromo-3-formyl-phenoxy)-2-dimethylamino-nicotinonitrile (5)

A mixture of 6-(4-bromo-3-formyl-phenoxy)-2-chloro-nicotinonitrile (3)and 2-(4-bromo-3-formyl-phenoxy)-6-chloro-nicotinonitrile (4) in a ratioof 2:1, respectively (2.47 g, 7.34 mmol) was dissolved in1,2-dichloroethane (40 mL) in a sealable reaction vessel. Thendimethylamine (18.3 mL, 36.7 mmol) was added and the reaction vessel wassealed with a teflon cap. The reaction was heated at 70° C. for 4 hr[Note: A white precipitate formed overtime]. The reaction mixture wascooled to room temperature and then concentrated to give an orangecoloured solid which contained a mixture of6-(4-bromo-3-formyl-phenoxy)-2-dimethylamino-nicotinonitrile (5) and2-(4-bromo-3-formyl-phenoxy)-6-dimethylamino-nicotinonitrile (6) in aratio of 2:1, respectively (2.80 g). The solid was dissolved with CH₂Cl₂(200 mL) followed by the addition of silica gel (50 g, 230-400 mesh) andconcentrated to dryness. This was loaded onto a silica gel column (100g, 230-400 mesh) and eluted with gradient 5-10% EtOAc/hexanes. Purefractions were combined and concentrated to give the title compound (5)as a white solid (1.10 g, 43% isolated yield).

6-(4-bromo-3-formyl-phenoxy)-2-dimethylamino-nicotinonitrile (5) ¹H NMR400 MHz (CDCl₃) δ 10.34 (s, 1H), 7.78 (d, J=2.7 Hz, 1H), 7.72 (d, J=8.2Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.27 (dd, J=8.6, 2.7 Hz, 1H), 6.24 (d,J=8.2 Hz, 1H), 3.11 (s, 6H).

2-(4-bromo-3-formyl-phenoxy)-6-dimethylamino-nicotinonitrile (6) ¹H NMR400 MHz (CDCl₃) δ10.35 (s, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.66 (d, J=8.6Hz, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.32 (dd, J=8.6, 2.7 Hz, 1H), 6.19 (d,J=8.6 Hz, 1H), 2.95 (s, 6H).

2-Dimethylamino-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(7)

6-(4-Bromo-3-formyl-phenoxy)-2-dimethylamino-nicotinonitrile (5) (1.10g, 3.18 mmol), bis(pinacolato)diboron (1.21 g, 4.77 mmol) and potassiumacetate (624 mg, 6.36 mmol) in a mixture ofdimethylformamide:1,2-dimethoxyethane (20 mL:20 mL) in a sealablereaction vessel was heated at 90° C. for 5 min. Then PdCl₂(dppf) (233mg, 0.32 mmol) was added, the teflon cap was replaced and the reactionwas heated at 90° C. for 3 hr. The reaction was left to cool to roomtemperature, then diluted with benzene (600 mL) and concentrated to givea black oil (3.0 g). The oil was diluted with CH₂Cl₂ (300 mL) followedby the addition of silica gel (30 g, 230-400 mesh) and concentrated todryness. This was loaded onto a silica gel column (60 g, 230-400 mesh)and eluted with gradient 10-40% EtOAc/hexanes. Pure fractions werecombined and concentrated to give the title compound (7) as an oil whichlater solidified to give a white solid (530 mg, 42% isolated yield). ¹HNMR 400 MHz (CDCl₃) δ 10.61 (s, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.78 (d,J=2.3 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.35 (dd, J=8.2, 2.3 Hz, 1H),6.20 (d, J=8.2 Hz, 1H), 3.08 (s, 6H), 1.28 (s, 12H).

19cx2-Dimethylamino-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D95)

A solution of2-dimethylamino-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(7) (370 mg, 0.94 mmol) in CH₂Cl₂ (5 mL) was added to a mixture of NaBH₄(26 mg, 0.66 mmol) in anhydrous methanol (10 mL) at room temperature.Additional solid NaBH₄ (82 mg, 2.2 mmol) was then added portionwise overa period of 10 minutes. The reaction mixture was then stirred for afurther 1 h at room temperature. The reaction was quenched by theaddition of a solution of glacial acetic acid (0.2 mL) and distilledwater (0.2 mL) followed by stirring for 10 minutes. The reaction wasconcentrated to give an oil (˜550 mg). The oil was dissolved in amixture of acetic acid/methanol/CH₂Cl₂ (1/2/100 v/v/v, 100 mL) followedby the addition of silica gel (5 g, 230-400 mesh) and concentrated todryness to give a free flowing impregnated silica. This was loaded ontoa silica column (10 g, 230-400 mesh) and eluted with aceticacid/methanol/CH₂Cl₂ (1/2/100 v/v/v). The fractions containing D95 werecollected and concentrated to give a light yellow coloured oil. The oilwas freeze dried by first diluting with MeOH/CH₂Cl₂ (1/1 v/v, 15 mL)followed by the addition of deionised water (200 mL), the resultantwhite suspension was frozen in a dry-ice acetone bath and placedovernight on freeze-dryer. A white solid of D95 was obtained (70 mg, 25%isolated yield). ¹H NMR 400 MHz (d₆-DMSO) δ9.23 (s, 1H), 7.95 (d, J=8.6Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.23 (d, J=0.5 Hz, 1H), 7.16 (dd,J=7.8, 0.5 Hz, 1H), 6.31 (d, J=8.6 Hz, 1H), 4.98 (s, 2H), 3.14 (s, 6H).Mass Spectrum [M+H⁺]=296. HPLC purity 95.04% (Maxplot), 94.63% (220 nm),92.41% (254 nm).

19cy6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrile(D96)

6-Chloro-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinamide (3)

To a solution of 2,6-dichloro-nicotinamide (1) (10 g, 52.9 mmol) inacetonitrile (anhydrous, 200 mL) was added(2-methoxy-ethyl)-methyl-amine (2) (18.8 g, 212 mmol). The reaction washeated at 60° C. for 1.5 hours. 5% NaOH solution (1000 mL) was slowlyadded. The solution was then extracted with EtOAc (3×250 mL). Thecombined organic layer was dried over MgSO₄, filtered, and evaporated invacuo. Purification was accomplished by silica gel chromatography,eluting with 5%-30% EtOAc/hexanes gradient, to afford 11.66 g (91%yield) of the title compound. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.07(d, J=8.6 Hz, 1H), 7.76 (br. s., 1H), 6.93 (d, J=8.2 Hz, 1H), 5.66 (br.s., 1H), 3.66-3.51 (m, 4H), 3.32 (s, 3H), 2.93 (s, 3H).

6-Chloro-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrile (4)

To a solution of6-chloro-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinamide (3) (14 g, 58mmol) in acetonitrile (anhydrous, 360 mL) were added pyridine (37.5 mL,463.8 mmol) and POCl₃ (21.2 mL, 232 mmol). The reaction was heated at55° C. for 3 hours. After cooling to room temperature, NaOH solution(10% aq.) was slowly added till pH 9. The solution was extracted withEtOAc (3×200 mL). The combined organic layer was dried over MgSO₄,filtered, and evaporated in vacuo. Purification was accomplished bysilica gel chromatography, eluting with 5%-30% EtOAc/hexanes gradient,to afford 11.6 g (90% yield) of the desired product. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.61 (d, J=7.4 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H), 3.87(t, J=5.3 Hz, 2H), 3.64 (t, J=5.3 Hz, 2H), 3.38 (s, 3H), 3.36 (s, 3H).

6-(4-Bromo-3-formyl-phenoxy)-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrile(6)

To a solution of6-chloro-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrile (4) (11.6 g,51.9 mmol) in DMF (anhydrous, 300 mL) were added2-bromo-5-hydroxy-benzaldehyde (10.4 g, 51.9 mmol) and K₂CO₃ (14.3 g,103.8 mmol). The reaction was heated at 80° C. for 16 hours. DMF wasevaporated in vacuo. Purification was accomplished by silica gelchromatography, eluting with 5%-30% EtOAc gradient, to afford 15 g (75%yield) of the title compound. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.34(s, 1H), 7.75-7.69 (m, 2H), 7.67 (d, J=8.6 Hz, 1H), 7.28-7.23 (m, 1H),6.26 (d, J=8.6 Hz, 1H), 3.56 (t, J=5.5 Hz, 2H), 3.36 (t, J=5.5 Hz, 2H),3.25 (s, 3H), 3.24 (s, 3H).

6-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrile(7)

To a solution of6-(4-bromo-3-formyl-phenoxy)-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrile(6) (15 g, 38.5 mmol) in 1,4-dioxane (anhydrous, 360 mL) were addedbispinacolatodiboron (11.7 g, 46.2 mmol), PdCl₂(dppf) (2.8 g, 3.85 mmol)and KOAc (11.3 g, 115.3 mmol). The solution was stirred at r.t. with N₂bubbling for 30 minutes. Then the reaction was heated at 100° C. for 3hours. After the reaction, the solution was filtered and concentrated invacuo. Purification was accomplished by silica gel chromatography,eluting with 2.5%-20% EtOAc/hexanes gradient, to afford 15 g (89% yield)of the title compound. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.64 (s,1H), 7.94 (d, J=7.8 Hz, 1H), 7.76 (d, J=2.3 Hz, 1H), 7.72-7.69 (m, 1H),7.35 (dd, J=8.0, 2.5 Hz, 1H), 6.25 (d, J=8.6 Hz, 1H), 3.56 (t, J=5.5 Hz,2H), 3.36 (t, J=5.5 Hz, 2H), 3.25 (s, 3H), 3.22 (s, 3H), 1.40 (s, 12H)

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrile(D96)

To a clear solution of6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrile(7) (15 g, 343 mmol) in MeOH (anhydrous, 300 mL) was slowly added NaBH₄(7.83 g, 206 mmol). The reaction was stirred at room temperature 4hours, before the addition of HCl solution (1 M, 200 mL). The stirringwas kept at room temperature overnight. Then the solution was slowlyevaporated in vacuo. Purification was accomplished by reverse phaseBiotage with 10%-100% MeOH/H₂O gradient to afford 3 g (26% yield) of thetitle compound. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.74 (d, J=8.6 Hz,1H), 7.70 (d, J=8.2 Hz, 1H), 7.13-7.09 (m, 2H), 6.23 (d, J=8.2 Hz, 1H),5.08 (s, 2H), 4.78 (s, 1H), 3.56 (t, J=5.7 Hz, 2H), 3.36 (t, J=5.7 Hz,2H), 3.27 (s, 3H), 3.23 (s, 3H); ES-MS: m/z 340 (M+H)⁺; HPLC: 99.38%(220 nm), 98.71% (MaxPlot).

19cz6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-pyrrolidin-1-yl-nicotinonitrile(D97)

6-(4-Bromo-3-formyl-phenoxy)-2-chloro-nicotinonitrile (3)

2,6-Dichloronicotinonitrile (7.42 g, 42.9 mmol),2-bromo-5-hydroxybenzaldehyde (7.84 g, 39.0 mmol) and triethylamine(7.89 g, 11.0 mL, 78.0 mmol) in 1,2-dichloroethane (50 mL) in a sealedreaction vessel was heated to 70° C. for 18 h. The reaction was cooledto room temperature and concentrated to give a mixture of6-(4-bromo-3-formyl-phenoxy)-2-chloro-nicotinonitrile (3) and2-(4-bromo-3-formyl-phenoxy)-6-chloro-nicotinonitrile (4) in a ratio of1.8:1, respectively (18 g). TLC of 3 gave R_(f)=0.4 and 4 gaveR_(f)=0.35 when eluted with 25% EtOAc/hexanes and rendered with UV lamp.The mixture was fractionated by dry-pack column chromatography asfollows: The oil was diluted with CH₂Cl₂ (200 mL) followed by theaddition of silica gel (70 g, 230-400 mesh) and concentrated to dryness.This was loaded onto a silica column (70 g, 230-400 mesh) and elutedwith gradient 5-40% EtOAc/hexanes. Three major fractions wherecollected; fraction 1 with 3:4 in ratio 1:1.5 (3.40 g), fraction 2 with3:4 in ratio 1.8:1 (3.70 g) and fraction 3 with 3:4 in ratio 2.0:1 (2.10g). Fraction 3, which was the most enriched fraction in desired compound3, was carried forward without further purification.

Compound 3: ¹H NMR 400 MHz (CDCl₃) δ10.34 (s, 1H), 7.99 (d, J=8.6 Hz,1H), 7.73 (d, J=8.6 Hz, 1H), 7.69 (d, J=2.7 Hz, 1H), 7.30 (dd, J=8.9,2.3 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H).

Compound 4: ¹H NMR 400 MHz (CDCl₃) δ10.34 (s, 1H), 7.97 (d, J=7.8 Hz,1H), 7.75 (d, J=10.5 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.34 (dd, J=9.0,3.1 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H).

6-(4-Bromo-3-formyl-phenoxy)-2-pyrrolidin-1-yl-nicotinonitrile (5)

A mixture of 6-(4-bromo-3-formyl-phenoxy)-2-chloro-nicotinonitrile (3):2-(4-bromo-3-formyl-phenoxy)-6-chloro-nicotinonitrile (4) in a ratio of2.0:1 (1.14 g, 3.39 mmol) and pyrrolidine (723 mg, 0.85 mL, 10.2 mmol)in 1,2-dichloroethane (30 mL) in a sealed reaction vessel was heated to80° C. for 90 min. The reaction was cooled to room temperature andconcentrated to give a mixture of6-(4-bromo-3-formyl-phenoxy)-2-pyrrolidin-1-yl-nicotinonitrile (5) and2-(4-bromo-3-formyl-phenoxy)-6-pyrrolidin-1-yl-nicotinonitrile (6) in aratio of 2:1 (2.10 g). TLC of6-(4-bromo-3-formyl-phenoxy)-2-pyrrolidin-1-yl-nicotinonitrile (5) gaveR_(f)=0.6 and2-(4-bromo-3-formyl-phenoxy)-6-pyrrolidin-1-yl-nicotinonitrile (6) gaveR_(f)=0.4 when eluted with 25% EtOAc/hexanes and rendered with UV lampor a solution of phosphomolybdic acid in ethanol. The mixture wasfractionated by dry-pack column chromatography as follows: The oil wasdiluted with 10% MeOH/CH₂Cl₂ (100 mL) followed by the addition of silicagel (10 g, 230-400 mesh) and concentrated to dryness. This was loadedonto a silica column (30 g, 230-400 mesh) and eluted with 10%EtOAc/hexanes. The mixture was separable and gave 5 (550 mg, whitesolid, 43% yield) and 6 (120 mg, white solid, 10% yield).

Compound 5: ¹H NMR 400 MHz (CDCl₃) δ10.34 (s, 1H), 7.79 (d, J=3.1 Hz,1H), 7.69 (d, J=8.2 Hz, 1H), 7.65 (d, J=8.6 Hz. 1H), 7.28 (dd, J=9.0,3.1 Hz, 1H), 6.18 (d, J=8.2 Hz, 1H), 3.60-3.52 (4H), 1.93-1.87 (4H).

Compound 6: ¹H NMR 400 MHz (CDCl₃) δ10.35 (s, 1H), 7.88 (d, J=2.7 Hz,1H), 7.66 (d, J=8.6 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.33 (dd, J=8.2,2.7 Hz, 1H), 6.05 (d, J=8.6 Hz, 1H), 3.40-3.20 (4H), 2.13-1.81 (4H).

6-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-pyrrolidin-1-yl-nicotinonitrile(7)

6-(4-Bromo-3-formyl-phenoxy)-2-pyrrolidin-1-yl-nicotinonitrile (5) (505mg, 1.36 mmol), bispinacolatodiboron (689 mg, 2.71 mmol) and KOAc (333mg, 3.39 mmol) in a mixture of DMF (5 mL) and 1,2-dimethoxyethane (15mL) in a sealed reaction vessel was heated to 90° C. for 5 min.PdCl₂(dppf) (99 mg, 0.13 mmol) was then added and the reaction mixturewas stirred vigorously at 90° C. for 3 h. The reaction was cooled toroom temperature and diluted with benzene (300 mL) and concentrated togive a black solid which contained product 7 (1.70 g) [Note: addition ofbenzene followed by evaporation allowed for the azeotropic removal ofDMF]. TLC of 7 gave R_(f)=0.4 when eluted with 25% EtOAc/hexanes andrendered with UV lamp or a solution of phosphomolybdic acid in ethanol.The crude black solid was fractionated by dry-pack column chromatographyas follows: The solid was dissolved with 10% MeOH/CH₂Cl₂ (200 mL)followed by the addition of silica gel (10 g, 230-400 mesh) andconcentrated to dryness. This was loaded onto a silica column (30 g,230-400 mesh) and eluted with 10% EtOAc/hexanes. Isolated 7 as a whitesolid (308 mg, 54%). ¹H NMR 400 MHz (CDCl₃) δ 10.62 (s, 1H), 7.93 (d,J=8.2 Hz, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.38 (dd,J=8.2, 2.3 Hz, 1H), 6.17 (d, J=8.2 Hz, 1H), 3.60-3.51 (4H), 1.93-1.83(4H), 1.41 (s, 12H).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-pyrrolidin-1-yl-nicotinonitrile(D97)

A solution of NaBH₄ (35 mg, 0.93 mmol) in MeOH (5 mL) was added to asolution of6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-pyrrolidin-1-yl-nicotinonitrile(7) (250 mg, 0.60 mmol) in CH₂Cl₂ (2.5 mL) at room temperature and thereaction was stirred for 5 minutes. Additional NaBH₄ solid (100 mg, 2.64mmol) was added in portions over 25 minutes and the reaction was stirredfor another 60 minutes at room temperature. A solution of glacial aceticacid (0.2 mL) in distilled water (0.2 mL) was added and the reaction wasstirred for 15 minutes at room temperature. The reaction mixture wasconcentrated to dryness and dried under high vacuum to give 450 mg of awhite solid. The white solid was fractionated by dry-pack columnchromatography as follows: The solid was dissolved in AcOH/MeOH/CH₂Cl₂(1:1:100, 200 mL) followed by the addition of silica gel (10 g, 230-400mesh) and concentrated to dryness. This was loaded onto a silica column(20 g, 230-400 mesh) and eluted with AcOH/MeOH/CH₂Cl₂ (1:1:100).Isolated was D97 as a white sticky solid (110 mg). This sticky solid wasdissolved in 30% MeOH/CH₂Cl₂ (30 mL) followed by addition of distilledwater (300 mL) and freeze dried to give a free-flowing white solid D97(90 mg, 47% yield). ¹H NMR 400 MHz (CDCl₃) δ9.19 (s, 1H), 7.89 (d, J=8.6Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.20 (br s, 1H), 7.13 (br d, J=7.8 Hz,1H), 6.22 (d, J=8.6 Hz, 1H), 4.96 (s, 2H), 3.48-3.40 (4H), 1.86-1.77(4H); Mass Spectrum (M+H)⁺=322; HPLC purity 96.73% (Maxplot), 97.50%(220 nm), 97.63% (254 nm).

19da2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile(D98)

4-Bromo-3-[1,3]dioxolan-2-yl-phenol (2)

To a solution of 2-bromo-5-hydroxy-benzaldehyde (1) (10 g, 49.8 mmol) intoluene (200 mL) were added ethylene glycol (9.25 g, 149.3 mmol) andcatalytic amount of p-TsOH (200 mg). After attaching a Dean-Stark trap,the reaction was heated at 136° C. for 3 hours. After the solution wascooled to room temperature, it was washed with saturated NaHCO₃ (200mL). The organic layer was dried over Na₂SO₄, filtered and evaporated invacuo to provide the 11.6 g (95% yield) of the title compound. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.40 (d, J=8.6 Hz, 1H), 7.09 (d, J=3.1 Hz,1H), 6.72 (dd, J=8.6, 3.1 Hz, 1H), 6.04 (s, 1H), 4.18-4.04 (m, 4H)

6-(4-Bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile+2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile(4+5)

To a solution of 2,6-dichloro-nicotinonitrile (3) (7.06 g, 40.8 mmol) inacetonitrile (anhydrous, 300 mL) were added4-bromo-3-[1,3]dioxolan-2-yl-phenol (2) (10 g, 40.8 mmol) and K₂CO₃(5.63 g, 40.8 mmol). The reaction was heated at 65° C. for 3 hours. Thesolution was filtered and evaporated in vacuo to afford 15.6 g of theproduct mixture. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=9.0 Hz,2H), 7.62 (d, J=8.6 Hz, 2H), 7.46 (d, J=3.1 Hz, 1H), 7.41 (d, J=3.1 Hz,1H), 7.18-7.08 (m, 2H), 7.05 (dd, J=8.8, 2.93 Hz, 1H), 6.93 (d, J=8.2Hz, 1H), 6.11 (s, 1H), 6.09 (s, 1H), 4.19-3.99 (m, 8H).

2-(4-Bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile(8)

To a solution of compound mixture,6-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile and2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile, (4+5,1 g, 2.6 mmol) in acetonitrile (anhydrous, 30 mL) was added2-methylamino-ethanol (6, 2.1 mL, 26 mmol). The reaction was heated at80° C. for 2 hours. After the reaction, all volatile components wereevaporated under vacuum. Purification was accomplished by silica gelchromatography, eluting with 10%-80% EtOAc/Hexane gradient, affordingthe title compound 400 mg in 36% yield. ¹H NMR 400 MHz (CDCl₃) δ 7.62(d, J=8.6 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.47 (d, J=3.1 Hz, 1H), 7.06(dd, J=8.6 Hz, 3.1 Hz, 1H), 6.18 (d, J=8.6 Hz, 1H), 6.08 (s, 1H),4.20-4.02 (m, 4H), 3.55 (t, J=3.2 Hz, 2H), 3.42 (t, J=3.2 Hz, 2H), 3.02(s, 3H).

2-(4-Bromo-3-formyl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile(9)

To a solution of2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile(8) (400 mg, 0.95 mmol) in THF (30 mL) was added HCl solution (1 M, 10mL). The reaction was stirred at room temperature overnight. After thereaction, all THF was evaporated under vacuum. The aqueous solution wasextracted with EtOAc (2×50 mL). The organic layer was washed with water(3×50 mL). The organic layer was dried over MgSO₄, filtered andevaporated under vacuum to afford the desired product 320 mg (89% yield)that was used without further purification. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 10.35 (s, 1H), 7.91 (d, J=2.7 Hz, 1H), 7.67 (t,J=9.2 Hz, 2H), 7.32 (dd, J=8.6, 2.7 Hz, 1H), 6.24 (d, J=8.6 Hz, 1H),3.70-3.62 (m, 2H), 3.56-3.49 (m, 2H), 3.04 (s, 3H).

2-(4-Bromo-3-formyl-phenoxy)-6-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-nicotinonitrile:(10)

To a solution of2-(4-bromo-3-formyl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile(9) (400 mg, 1.06 mmol) in THF (anhydrous, 30 mL) were added TBDMS-Cl(193 mg, 1.28 mmol) and Et₃N (0.178 mL, 1.28 mmol). The solution wasstirred at room temperature for 2 days. The solution was filtered andconcentrated in vacuo. Purification was accomplished by silica gelchromatography, eluting with 2.5%-20% EtOAc/hexanes gradient, to afford420 mg (81% yield) of the title compound. ¹H NMR 400 MHz (CDCl₃) δ 10.4(s, 1H), 7.83 (s, 1H), 7.76-7.68 (m, 2H), 7.40-7.33 (m, 1H), 6.30 (br s,1H), 3.62 (br s, 2H), 3.48 (s, 2H), 3.02 (s, 3H), 0.89 (s, 9H), 0.02 (s,6H).

6-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-2-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile:(11)

To a solution of2-(4-bromo-3-formyl-phenoxy)-6-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-nicotinonitrile(10) (520 mg, 1.06 mmol) in 1,4-dioxane (anhydrous, 60 mL) were addedbispinacolatodiboron (323 mg, 1.27 mmol), PdCl₂(dppf) (78 mg, 0.106mmol) and KOAc (312 mg, 3.18 mmol). The solution was stirred at r.t.with N₂ bubbling for 30 minutes. Then the reaction was heated at 100° C.for 3 hours. The solution was filtered and concentrated in vacuo.Purification was accomplished by silica gel chromatography, eluting with2.5%-20% EtOAc/hexanes gradient to afford 485 mg (85% yield) of thetitle compound. ¹H NMR 400 MHz (CDCl₃) δ 10.6 (s, 1H), 7.93 (d, J=8.6Hz, 1H), 7.82 (s, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.39 (d, J=8.6 Hz, 1H),6.20 (br s, 1H), 3.52 (br s, 2H), 3.39 (s, 2H), 2.98 (s, 3H), 1.37 (s,12H), 0.79 (s, 9H), −0.09 (s, 6H).

2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile:(D98)

To a clear solution of6-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-2-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(11) (485 mg, 0.903 mmol) in MeOH (anhydrous, 100 mL) was slowly addedNaBH₄ (101 mg, 2.65 mmol). The reaction was stirred at room temperaturefor 4 hours, before the addition of HCl solution (1 M, 60 mL). Thestirring was kept at room temperature overnight. Then the solution wasslowly evaporated in vacuo. Purification was accomplished by reversephase Biotage with 10%-100% MeOH/H₂O gradient to afford 51 mg (13.8%yield) of the desired product. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.22 (s,1H), 7.92 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.24 (s, 1H), 7.16(dd, J=7.8, 2.0 Hz, 1H), 6.43 (br. s., 1H), 4.98 (s, 2H), 3.90 (br. s.,1H), 3.47 (br. s., 2H), 3.39 (s, 2H, masked), 2.95 (br. s., 3H); HPLC:98.18% (220 nm), 99.15% (254 nm), 99.16 (MaxPlot).

19db6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-(2-hydroxy-ethoxy)-nicotinonitrile(D99)

6-Chloro-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (2a)

To a solution of 2-(tetrahydro-pyran-2-yloxy)-ethanol (12.65 mL, 86.70mmol) in DMF (50 mL) at 0° C. was added sodium hydride (95% in mineraloil, 2.19 g, 86.70 mmol) portion-wise. After 1 h at room temperature,this mixture was slowly added to a solution of2,6-dichloro-nicotinonitrile (10.0 g, 57.80 mmol) in DMF (30 mL) at 0°C. After overnight, DMF was removed under reduced pressure, and theresulting mixture was diluted with EtOAc (200 mL), washed with water(2×25 mL) and brine (2×25 mL) solution, dried over anhydrous Na₂SO₄,filtered, and concentrated to give a mixture of regioisomers 2a and 2bas an oil, Purification was accomplished by flash chromatography onsilica gel using 2-25% EtOAc/hexanes gradient elution to yield the titlecompound (4.0 g, 26%) as a transparent oil. ¹H NMR (400 MHz, CDCl₃) δppm 7.89-7.75 (m, 1H), 7.08-6.96 (m, 1H), 4.74 (br. s., 1H), 4.63 (t,J=4.9 Hz, 2H), 4.19-4.00 (m, 1H), 3.98-3.74 (m, 2H), 3.62-3.43 (m, 1H),1.63-1.91 (m, 2H), 1.68-1.47 (m, 4H).

6-(4-Bromo-3-formyl-phenoxy)-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile(3)

To a mixture of6-chloro-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (2.4 g,8.48 mmol) and 2-bromo-5-hydroxy-benzaldehyde (1.87 g, 9.33 mmol) in DMF(25 mL) was added potassium carbonate (1.75 g, 12.69 mmol). Theresulting mixture was heated at 80° C. overnight. DMF was removed underreduced pressure, the residue was diluted with EtOAc (200 mL), washedwith water (20 mL) and brine (3×20 mL), dried over Na₂SO₄, filtered, andconcentrated to give white solid. Purification was accomplished by flashchromatography on silica gel using 5-25% EtOAc/hexanes as gradientelution yielding the title compound (2.7 g, 71%) as white solid. ¹H NMR(400 MHz, CDCl₃) δ ppm 10.35 (s, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.75 (d,J=2.7 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.28 (dd, J=8.6, 3.5 Hz, 1H),6.60 (d, J=8.2 Hz, 1H), 4.64 (s, 1H), 4.28 (t, J=4.9 Hz, 2H), 3.97-3.80(m, 2H), 3.72-3.60 (m, 1H), 3.55-3.42 (m, 1H), 1.84-1.64 (m, 2H),1.61-1.49 (m, 4H).

6-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile(4)

To a degassed solution of6-(4-bromo-3-formyl-phenoxy)-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile(2.7 g, 6.03 mmol) in 1,4-dioxane (25 mL) was addedbis(pinacolato)diboron (1.76 g, 6.94 mmol), potassium acetate (1.77 g,18.0 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride (0.22 g,0.30 mmol). After purging with N₂ again, the suspension was heated at80° C. for 3 h. The mixture was cooled to room temperature and passedthrough Celite® and diluted with EtOAc (150 mL), organic layer waswashed with water (20 mL) and brine (20 mL) solution, dried over Na₂SO₄,filtered, and concentrated. Purification was accomplished by flashchromatography on silica gel using 5-25% EtOAc/hexanes gradient elutionyielding the title compound (2.10 g, 72%) as white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.37 (s, 1H), 8.28 (d, J=8.6 Hz, 1H), 7.82 (d,J=8.2 Hz, 1H), 7.71 (s, 1H), 7.57 (d, J=8.2 Hz, 1H), 6.81 (d, J=8.2 Hz,1H), 4.51 (s, 1H), 4.29-4.10 (m, 2H), 3.85-3.60 (m, 2H), 3.60-3.50 (m,1H), 3.46-3.36 (m, 1H), 1.75-1.48 (m, 2H), 1.50-1.33 (m, 4H), 1.33 (s,12H).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-(2-hydroxy-ethoxy)-nicotinonitrile(D99)

To a solution of6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile(2.5 g, 5.15 mmol) in methanol (15 mL) at 0° C. was added sodiumborohydride (0.38 g, 10.32 mmol). After 1 h at rt, the solution wascooled in an ice bath and 2M HCl was added until pH reached to 3˜4. Theresulting mixture was stirred at 0° C. for 2 h and then at roomtemperature for 30 min. The solvent was removed under reduced pressurepurification was accomplished by reverse phase prep HPLC using CH₃CN/H₂O(0.1% AcOH) as the eluent to yield the title compound D99 (1.0 g, 40%)as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.23 (s, 1H), 8.22 (d,J=8.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J=8.2 Hz,1H), 6.66 (d, J=8.6 Hz, 1H), 4.97 (s, 2H), 4.82 (t, 1H), 4.12 (t, J=4.9Hz, 2H), 3.73-3.50 (m, 2H); MS (ES) m/z: 313 (M+1)⁺; HPLC purity 98.78%(Maxplot), 98.58% (220 nm).

19dc2-Cyclopentyloxy-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D100)

6-Chloro-2-cyclopentyloxy-nicotinamide (2)

To a solution of cyclopentanol (1.42 mL, 15.70 mmol) in DMF (5 mL) at 0°C. was added sodium hydride (95% in mineral oil, 0.39 g, 15.70 mmol) inportions and stirred for 1 h at room temperature. This mixture wasslowly added to a solution of 2,6-dichloro-nicotinamide (2.0 g, 10.47mmol) in DMF (10 mL) at 0° C. The reaction mixture was stirred at roomtemperature overnight. DMF was removed under reduced pressure, and theresulting mixture was diluted with EtOAc (100 mL), washed with water(2×25 mL) and brine (2×25 mL) solution, dried over anhyd. Na₂SO₄,filtered, and concentrated to give yellow oil, which was purified byflash chromatography on silica gel using 10-25% EtOAc/hexanes as eluentto yield the title compound (1.94 g, 51%) as a transparent oil. ¹H NMR(400 MHz, CDCl₃) δ 8.44 (d, J=7.8 Hz, 1H), 7.65 (br. s., 1H), 7.03 (d,J=8.2 Hz, 1H), 5.74 (br. s., 1H), 5.70-5.57 (m, 1H), 2.25-1.95 (m, 2H),1.90-1.66 (m, 6H).

6-Chloro-2-cyclopentyloxy-nicotinonitrile (3)

To a solution of 6-chloro-2-cyclopentyloxy-nicotinamide (1.56 g, 6.48mmol) and pyridine (3.14 mL, 38.88 mmol) in acetonitrile (30 mL),phosphorus oxychloride (1.77 mL, 19.44 mmol) was added over a period of5 min. The reaction was stirred at 55° C. for 1 h. Acetonitrile wasevaporated in vacuo and the resulting residue was then neutralized with1N NaOH at 0° C. until pH reached to 7. The reaction mixture wasextracted with EtOAc (100 mL). The organic layer was collected and theaqueous was further extracted with EtOAc (3×50 mL). All organics werecombined washed with brine (2×25 mL), dried over anhyd. Na₂SO₄,filtered, and concentrated to give the title compound (1.63 g, 94%) asyellow oil, which was carried forward without further purification. ¹HNMR (400 MHz, DMSO-d₆) δ 8.26 (d, J=7.8 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H),5.49-5.42 (m, 1H), 2.25-1.78 (m, 2H), 1.80-1.64 (m, 4H), 1.60 (t, J=6.8Hz, 2H).

6-(4-Bromo-3-formyl-phenoxy)-2-cyclopentyloxy-nicotinonitrile (4)

To a mixture of 6-chloro-2-cyclopentyloxy-nicotinonitrile (1.32 g, 5.92mmol) and 2-bromo-5-hydroxy-benzaldehyde (1.43 g, 7.10 mmol) in DMF (10mL) was added potassium carbonate (1.22 g, 8.88 mmol). The resultingmixture was heated at 69° C. overnight. DMF was removed under reducedpressure, the residue was diluted with EtOAc (100 mL), washed with water(30 mL) and brine (30 mL), dried over Na₂SO₄, filtered, and concentratedto give white solid, which was purified by flash chromatography onsilica gel using 10-25% EtOAc/hexanes as eluent to yield the titlecompound (2.30 g, quantitative) as white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.19 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.88 (d, J=8.6 Hz,1H), 7.70 (s, 1H), 7.60-7.46 (m, 1H), 6.79 (d, J=8.2 Hz, 1H), 4.95 (br.s., 1H), 1.87-1.50 (m, 6H), 1.52-1.30 (m, 2H).

2-Cyclopentyloxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(5)

To a degassed solution of6-(4-bromo-3-formyl-phenoxy)-2-cyclopentyloxy-nicotinonitrile (2.20 g,5.68 mmol) in 1,4-dioxane (25 mL) was added bis(pinacolato)diboron (1.73g, 6.81 mmol), potassium acetate (1.67 g, 17.04 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride (0.20 g,0.28 mmol). Degassed again, and the suspension was heated at 80° C.overnight. The mixture was passed through Celite washed with EtOAc (100mL), organic layer was washed with water (30 mL) and brine (30 mL)solution, dried over Na₂SO₄, filtered, and concentrated to give crudeproduct, which was purified by flash chromatography on silica gel using10-25% EtOAc/hexanes as eluent to yield the title compound (2.0 g, 83%)as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H), 8.24 (d,J=8.2 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.74 (s, 1H), 7.56 (d, J=8.2 Hz,1H), 6.78 (d, J=8.2 Hz, 1H), 4.96 (br. s., 1H), 1.80-1.54 (m, 6H),1.50-1.40 (m, 2H), 1.34 (s, 12H).

2-Cyclopentyloxy-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D100)

To a solution of2-cyclopentyloxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(2.0 g, 4.60 mmol) in methanol (15 mL) at 0° C. was added sodiumborohydride (0.26 g, 6.90 mmol). After 1 h at rt, 2 M HCl was added toit at 0° C. until pH reached to 3˜4. The resulting mixture was stirredat 0° C. for 30 min and then sonicated to give white solid which wasfiltered and lyophilized to yield D100 (0.85 g, 56%) as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.20 (d, J=8.2 Hz, 1H), 7.77 (d,J=7.8 Hz, 1H), 7.27 (d, J=1.2 Hz, 1H), 7.18 (dd, J=8.2, 1.9 Hz, 1H),6.69 (d, J=8.2 Hz, 1H), 4.97 (br. s., 3H), 1.75-1.54 (m, 6H), 1.52-1.33(m, 2H); MS (ES) m/z: 337 (M+1)⁺; HPLC purity 99.36% (Maxplot), 99.35%(220 nm); Elemental analysis for C₁₈H₁₇BN₂O₄.0.25H₂O: CalculatedC=63.46%, H=5.18%, N=8.22%. Found C=63.34%, H=5.17%, N=8.34%.

19dd2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-6-(2-methoxy-ethylamino)-nicotinonitrile(D101)

4-Bromo-3-[1,3]dioxolan-2-yl-phenol (2)

To a solution of 2-bromo-5-hydroxy-benzaldehyde (1) (10 g, 49.8 mmol) intoluene (200 mL) were added ethylene glycol (9.25 g, 149.3 mmol) andcatalytic amount of p-TsOH (200 mg). After attaching a Dean-Stark trap,the reaction was heated at 136° C. for 3 hours. After the solutioncooled to room temperature, it was washed with saturated NaHCO₃ (200mL). The organic layer was dried over Na₂SO₄, filtered and evaporated invacuo to provide 11.6 g (95% yield) of the title compound. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 7.40 (d, J=8.6 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H),6.72 (dd, J=8.6, 3.1 Hz, 1H), 6.04 (s, 1H), 4.18-4.04 (m, 4H)

6-(4-Bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile+2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile(4+5)

To a solution of 2,6-dichloro-nicotinonitrile (3) (7.06 g, 40.8 mmol) inacetonitrile (anhydrous, 300 mL) were added4-bromo-3-[1,3]dioxolan-2-yl-phenol (2) (10 g, 40.8 mmol) and K₂CO₃(5.63 g, 40.8 mmol). The reaction was heated at 65° C. for 3 hours. Thesolution was filtered and evaporated in vacuo to afford 15.6 g of themixture. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.94 (d, J=9.0 Hz, 2H),7.62 (d, J=8.6 Hz, 2H), 7.46 (d, J=3.1 Hz, 1H), 7.41 (d, J=3.1 Hz, 1H),7.18-7.08 (m, 2H), 7.05 (dd, J=8.8, 2.93 Hz, 1H), 6.93 (d, J=8.2 Hz,1H), 6.11 (s, 1H), 6.09 (s, 1H), 4.19-3.99 (m, 8H).

2-(4-Bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-(2-methoxy-ethylamino)-nicotinonitrile(8)

To a solution of compound mixture,6-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile and2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile (4+5,2.5 g, 6.6 mmol) in acetonitrile (anhydrous, 50 mL) was added2-methoxy-ethylamine (5.7 mL, 66 mmol). The reaction was heated at 80°C. for 2 hours. After the reaction, all volatile components wereevaporated under vacuum. Purification was achieved by silica gelchromatography, eluting with 10%-80% EtOAc/hexanes gradient, affording1.0 g (36% yield) of the title compound. ¹H NMR (400 MHz, chloroform-d)δ ppm 7.58-7.47 (m, 2H), 7.41 (d, J=3.1 Hz, 1H), 7.04 (dd, J=8.6, 2.7Hz, 1H), 6.09-6.03 (m, 2H), 5.37 (t, J=5.1 Hz, 1H), 4.14-3.99 (m, 4H),3.37 (t, J=5.1 Hz, 2H), 3.31-3.23 (m, 5H).

2-(4-Bromo-3-formyl-phenoxy)-6-(2-methoxy-ethylamino)-nicotinonitrile(9)

To a solution of2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-(2-methoxy-ethylamino)-nicotinonitrile(8) (1.0 g, 2.38 mmol) in THF (50 mL) was added HCl solution (IM/H₂O, 20mL). After overnight, the THF was evaporated under vacuum. The aqueoussolution was extracted with EtOAc (2×50 mL). The organic layer waswashed with water (3×50 mL), dried over MgSO₄, filtered and evaporatedin vacuo. Purification was accomplished by silica gel chromatography,eluting with 25%-100% EtOAc/hexanes gradient, to afford the desiredproduct 780 mg (87% yield) as a white solid. ¹H NMR (400 MHz,chloroform-d) δ ppm 10.34 (s, 1H), 7.80 (d, J=2.7 Hz, 1H), 7.67 (d,J=8.6 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.30 (dd, J=8.8, 2.9 Hz, 1H),6.13 (d, J=8.2 Hz, 1H), 5.24 (br. s., 1H), 3.42 (t, J=4.9 Hz, 2H),3.35-3.27 (m, 5H).

2-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-6-(2-methoxy-ethylamino)-nicotinonitrile(10)

To a solution of2-(4-bromo-3-formyl-phenoxy)-6-(2-methoxy-ethylamino)-nicotinonitrile(9) (780 mg, 2.0 mmol) in 1,4-dioxane (anhydrous, 100 mL) were addedbispinacolatodiboron (630 mg, 2.5 mmol), PdCl₂(dppf) (150 mg, 0.2 mmol)and KOAc (610 mg, 6.2 mmol). The solution was stirred at r.t. with N₂bubbling for 30 minutes. Then the reaction was heated at 100° C. for 3hours. After cooling to room temperature, the solution was filtered andconcentrated in vacuo. Purification was accomplished by silica gelchromatography, eluting with 25%-100% EtOAc/hexanes gradient to afford440 mg (50% yield) of the title compound product. ¹H NMR (400 MHz,chloroform-d) δ ppm 10.62 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.82 (d,J=2.0 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.40 (dd, J=8.2, 2.3 Hz, 1H),6.12 (d, J=8.6 Hz, 1H), 5.37 (t, J=4.9 Hz, 1H), 3.40 (t, J=4.9 Hz, 2H),3.33-3.25 (m, 5H), 1.40 (s, 12H).

2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-6-(2-methoxy-ethylamino)-nicotinonitrile(D101)

To a clear solution of2-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-6-(2-methoxy-ethylamino)-nicotinonitrile(10) (440 mg, 1.04 mmol) in MeOH (anhydrous, 100 mL) was slowly addedNaBH₄ (120 mg, 3.12 mmol). The reaction was stirred at room temperaturefor 4 hours, before the addition of HCl solution (1 M, 50 mL). Thestirring was kept at room temperature overnight. Then the solution wasslowly concentrated in vacuo. Purification was accomplished bypreparative HPLC to afford the title compound (108 mg, 32% yield) as awhite lyophilizate. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.23 (br. s., 1H),7.86 (br. s., 1H), 7.79-7.68 (m, 2H), 7.24 (s, 1H), 7.18-7.13 (m, 1H),6.30 (d, J=8.6 Hz, 1H), 4.98 (s, 2H), 3.20 (d, J=1.6 Hz, 2H), 3.17-3.06(m, 5H); ES-MS m/z=326 (M+H)⁺; HPLC: 99.39% (220 nm), 99.24% (MaxPlot).

19de6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-morpholin-4-yl-nicotinonitrile(D102)

6-Chloro-2-morpholin-4-yl-nicotinamide (2)

Refer to synthesis of (D46) for preparation of 2,6-dichloro-nicotinamide(1). A sealed reaction vessel containing 2,6-dichloro-nicotinamide (1)(1.85 g, 9.70 mmol) and morpholine (1.69 mL, 19.4 mmol) in anhydrousdimethylformamide (20 mL) was heated to 50° C. for 2.5 h. The reactionwas then cooled to room temperature and diluted with 0.1 M NaOH (600 mL)and extracted with ethyl acetate (3×500 mL). All organics were combined,dried over Na₂SO₄, filtered and concentrated to give the title compound(2.49 g) as an orange oil, which later solidified upon standing.Compound 6-Chloro-2-morpholin-4-yl-nicotinamide (2) was carried forwardwithout further purification. ¹H NMR 400 MHz (d₆-DMSO) δ7.89 (br s, 1H),7.67 (d, J=7.8 Hz, 1H), 7.56 (br s, 1H), 6.88 (d, J=7.8 Hz, 1H), 3.67(br t, J=4.7 Hz, 4H), 3.31 (br t, J=4.7 Hz, 4H).

6-Chloro-2-morpholin-4-yl-nicotinonitrile (3)

Experimental procedure for synthesis of6-chloro-2-morpholin-4-yl-nicotinonitrile (3) is the same as thatdescribed in synthesis of (D46). The reaction of6-chloro-2-morpholin-4-yl-nicotinamide (2) (2.49 g) with phosphorusoxychloride (2.7 mL, 29 mmol) and pyridine (4.7 mL, 58 mmol) inacetonitrile (60 mL) gave a crude black oil upon workup. The black oilwas fractionated by dry-pack column chromatography as follows: the oilwas diluted with CH₂Cl₂ (300 mL) followed by the addition of silica gel(20 g, 230-400 mesh) and concentrated to dryness. This was loaded onto asilica column (60 g, 230-400 mesh) and eluted with 10% EtOAc/hexanes.Pure fractions were combined and concentrated to give the title compoundas a white solid (1.97 g, 91% isolated yield over 2 steps with respectto 1.85 g of compound 1). TLC eluted with 50% EtOAc/hexanes and renderedwith UV lamp gave R_(f)=0.8; ¹H NMR 400 MHz (CDCl₃) δ7.69 (d, J=8.2 Hz,1H), 6.75 (d, J=7.8 Hz, 1H), 3.85-3.77 (8H).

6-(4′-Bromo-3′-formyl-phenoxy)-2-morpholin-4-yl-nicotinonitrile (5)

Experimental procedure for synthesis of6-(4′-bromo-3′-formyl-phenoxy)-2-morpholin-4-yl-nicotinonitrile (5) isthe same as that described in synthesis of D46 except that the reactionwas heated at 50° C. for 18 h. The reaction of6-chloro-2-morpholin-4-yl-nicotinonitrile (3) (1.58 g, 7.06 mmol),2-bromo-5-hydroxy-benzaldehyde (4) (2.13 g, 10.6 mmol) and K₂CO₃ (1.95g, 14.1 mmol) in DMF (30 mL) gave crude oil upon workup. The oil wasfractionated by dry-pack column chromatography as follows: the oil wasdiluted with CH₂Cl₂ (300 mL) followed by the addition of silica gel (40g, 230-400 mesh) and concentrated to dryness. This was loaded onto asilica column (80 g, 230-400 mesh) and eluted with gradient 10-20%EtOAc/hexanes. Pure fractions were combined and concentrated to give thetitle compound as a white solid (1.69 g, 61% isolated yield).

TLC eluted with 25% EtOAc/hexanes and rendered with UV lamp andphosphomolybdic acid solution gave R_(f)=0.4; ¹H NMR 400 MHz (CDCl₃) δ10.34 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.76 (d, J=3.1, 1H), 7.68 (d,J=9.0 Hz, 1H), 7.25 (dd, J=8.6, 3.1 Hz, 1H), 6.38 (d, J=8.2 Hz, 1H),3.71 (br t, J=4.3 Hz, 4H), 3.59 (br t, J=4.3 Hz, 4H).

6-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-morpholin-4-yl-nicotinonitrile(6)

Experimental procedure for synthesis of6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-morpholin-4-yl-nicotinonitrile(6) is the same as that described in synthesis of (D46). The reaction of5 (1.69 g, 4.37 mmol), bis(pinacolato)diboron (3.32 g, 13.1 mmol) andpotassium acetate (1.28 g, 13.1 mmol) in a solvent mixture ofdimethylformamide (10 mL) and 1,2-dimethoxyethane (40 mL) gave a brownoil. The brown oil was fractionated by dry-pack column chromatography asfollows: the oil was diluted with CH₂Cl₂ (400 mL) followed by theaddition of silica gel (40 g, 230-400 mesh) and concentrated to dryness.This was loaded onto a silica column (80 g, 230-400 mesh) and elutedwith gradient 10-20% EtOAc/hexanes. The pure fractions were combined andconcentrated to give the title compound as a white solid (1.24 g, 65%isolated yield). TLC with two elutions of 25% EtOAc/hexanes and renderedwith UV lamp gave R_(f)=0.3; ¹H NMR 400 MHz (CDCl₃) δ 10.64 (s, 1H),7.95 (d, J=8.2 Hz, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H),7.36 (dd, J=8.2, 2.3 Hz, 1H), 6.39 (d, J=8.2 Hz, 1H), 3.71 (br t, J=5.1Hz, 4H), 3.59 (br t, J=5.1 Hz, 4H), 1.40 (s, 12H).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-morpholin-4-yl-nicotinonitrile(D102)

Experimental procedure for synthesis of6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-morpholin-4-yl-nicotinonitrile(D102) is the same as that described in synthesis of (D46). The reactionof6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-morpholin-4-yl-nicotinonitrile(6) (1.20 g, 2.76 mmol) with NaBH₄ (417 mg, 11.0 mmol) gave an orangeoil containing D102 upon workup. The oil was fractionated by dry-packcolumn chromatography as follows: The oil was diluted with 30%MeOH/CH₂Cl₂ (400 mL) followed by the addition of silica gel (40 g,230-400 mesh) and concentrated to dryness. This was loaded onto a silicacolumn (120 g, 230-400 mesh) and eluted with 1:1:100 aceticacid:MeOH:CH₂Cl₂. The fractions containing D102 were collected andconcentrated to give a light yellow coloured oil. The oil was freezedried by first diluting with acetonitrile (40 mL) followed by theaddition of de-ionised water (400 mL), the resultant white suspensionwas frozen in a dry-ice acetone bath and placed overnight onfreeze-dryer. A white solid of D102 was obtained (740 mg, 94% purity byHPLC). To increase purity of D102, it was re-subjected to columnchromatography and freeze-dried following the same conditions as beforeto give D102 as a white solid (405 mg, 98% purity by HPLC, 44% isolatedyield). TLC eluted with 1:2:100 acetic acid:MeOH:CH₂Cl₂ and renderedwith UV lamp gave R_(f)=0.5; ¹H NMR 400 MHz (d₆-DMSO) δ9.23 (s, 1H),8.06 (d, J=8.6 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.25 (d, J=1.9 Hz, 1H),7.16 (dd, J=8.2, 1.9 Hz, 1H), 6.46 (d, J=8.6 Hz, 1H), 4.98 (s, 2H), 3.61(br t, J=4.5 Hz, 4H), 3.49 (br t, J=4.5 Hz, 4H); Mass Spectrum[M+H]=338; HPLC purity 96.50% (Maxplot), 98.28% (220 nm), 97.23 (254nm).

19df 5-(4-(methylsulfonyl)phenoxy)benzo[c][1,2]oxaborol-1 (3H)-ol (D103)Preparation of B

To the solution of A (15.4 g, 77 mmol), 2-bromo-5-hydroxybenzaldehyde(9.67 g, 48 mmol), 4 A MS (35 g) and Cu(OAc)₂ (11.32 g, 62.6 mmol) indry CH₂Cl₂ (250 ml) was added pyridine (6.84 g, 86.6 mmol) and Et₃N(12.2 ml, 86.6 mmol) under Ar. The reaction mixture was stirred atambient temperature overnight and filtrated, washed with 2N HCl,extracted with CH₂Cl₂. The organic layer was separated, dried (Na₂SO₄),filtered, and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: petroleum ether/EtOAc10/1 to 4/1). The pure fraction was collected, and the solvent wasevaporated to afford B (2.9 g, 7.8%): ¹H NMR (DMSO, 500 MHz): δ 10.17(1H, S), 7.95 (2H, d, J=8.5 Hz), 7.89 (1H, d, J=8.5 Hz), 7.49 (1H, d,J=2 Hz), 7.45 (1H, dd, J=2.0, 8.5 Hz), 7.27 (2H, d, J=8.5 Hz), 3.22 (3H,s).

Preparation of C

To the solution of B (4.0 g, 11.3 mmol) in MeOH (250 ml) was added NaBH₄(214 mg, 5.65 mmol). The reaction mixture was stirred at ambienttemperature for 0.5 h. The solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: petroleumether/EtOAc 2/1). The pure fraction was collected, and the solvent wasevaporated to afford C (3.25 g, 93%): ¹H NMR (DMSO, 500 MHz): δ 3.20(3H, s), 4.50 (2H, d, J=5.5 Hz), 5.55 (1H, t, J=5.5 Hz), 7.02 (1H, dd,J=3.0, 8.5 Hz), 7.20 (2H, m), 7.24 (1H, d, J=2.5 Hz), 7.65 (1H, d, J=8.5Hz), 7.93 (2H, m).

Preparation of D

To the solution of C (400 mg, 1.12 mmol) in dry DMF (6 ml) was added NaH(49 mg, 1.12 mmol, 55%) under Ar. The reaction mixture was stirred at 0°C. for 0.5 h, then (chloromethoxy)ethane (137 mg, 1.46 mmol) was added.The reaction mixture was stirred at ambient temperature for 1 h andquenched with i-PrOH. The solvent was evaporated under high vacuum. Theresidue was dissolved in EtOAc, washed with water. The organic layer wasseparated, dried (Na₂SO₄), filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:petroleum ether/EtOAc 5/1). The pure fraction was collected, and thesolvent was evaporated to afford D (350 mg, 75%): ¹H NMR (CDCl₃, 400MHz): δ 1.22 (3H, m), 3.05 (3H, s), 3.64 (2H, m), 4.65 (2H, s), 4.80(2H, s), 6.88 (1H, dd, J=3.2, 8.8 Hz), 7.08 (2H, m), 7.25 (1H, d, J=3.2Hz), 7.57 (1H, d, J=8.8 Hz), 7.89 (2H, m).

Preparation of E

A mixture of D (340 mg, 0.82 mmol), bis(pinacolato)diboron (625 mg, 2.46mmol), PdCl₂(dppf)₂ (19.8 mg, 0.0246 mmol) and KOAc (241 mg, 2.46 mmol)in 1,4-dioxane (5 mL) was stirred at 80 overnight under Ar. The organiclayer was removed. The residue was purified by column chromatographyover silica gel (eluent: petroleum ether/EtOAc 5/1). The pure fractionwas collected, and the solvent was evaporated to afford E (360 mg, 95%):¹H NMR (CDCl₃, 500 MHz): δ 1.20 (3H, t, J=4.5 Hz), 1.32 (12H, s), 3.05(3H, s), 3.63 (2H, m), 4.80 (2H, s), 4.87 (2H, s), 6.96 (1H, dd, J=2.5,10 Hz), 7.09 (2H, dd, J=2.5, 9.0 Hz), 7.20 (1H, d, J=3.0 Hz), 7.86 (3H,m).

Preparation of (D103)

A mixture of E (300 mg, 0.66 mmol) in 6 N HCl (6 mL) and THF (9 mL) wasstirred at ambient temperature overnight. The solvents were removed. Theresidue was purification by preparation HPLC to obtain the desiredcompound (100 mg, 50%): ¹H NMR (DMSO-d₆, 500 MHz): δ 3.20 (3H, s), 4.97(2H, s), 7.11 (1H, dd, J=2.0, 8.0 Hz), 7.16 (1H, d, J=1.5 Hz), 7.21 (2H,m), 7.80 (1H, d, J=8.0 Hz), 7.93 (2H, m), 9.23 (1H, s).

19dg 5-(4-(isopropylsulfonyl)phenoxy)benzo[c][1,2]oxaborol-1 (3H)-ol(D104) Preparation of B

To the solution of A (15.0 g, 65.8 mmol), 2-bromo-5-hydroxybenzaldehyde(8.26 g, 41.1 mmol), 4 A MS (35 g) and Cu(OAc)₂ (9.68 g, 53.4 mmol) indry CH₂Cl₂ (250 ml) was added pyridine (5.85 g, 74 mmol) and Et₃N (10.4ml, 74 mmol) under Ar. The reaction mixture was stirred at ambienttemperature overnight and filtrated, washed with 2N HCl, extracted withCH₂Cl₂. The organic layer was separated, dried (Na₂SO₄), filtered, andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: petroleum ether/EtOAc 10/1 to5/1). The pure fraction was collected, and the solvent was evaporated toafford B (2.2 g, 14%): ¹H NMR (DMSO, 500 MHz): δ 10.33 (1H, S), 7.86(1H, m), 7.85 (1H, m), 7.70 (1H, d, J=8.5 Hz), 7.61 (1H, d, J=3.0 Hz),7.21 (1H, dd, J=3.0 8.5 Hz), 7.11 (1H, m), 7.09 (1H, m), 3.19 (1H, m),1.32 (3H, s), 1.31 (3H, s).

Preparation of C

To the solution of B (2.9 g, 7.6 mmol) in MeOH (150 ml) was added NaBH₄(144 mg, 3.8 mmol). The reaction mixture was stirred at ambienttemperature for 0.5 h. The solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: petroleumether/EtOAc 3/1). The pure fraction was collected, and the solvent wasevaporated to afford C (2.6 g, 89%): ¹H NMR (DMSO, 500 MHz): δ 1.14 (3H,s), 1.15 (3H, s), 3.36 (1H, m), 4.50 (2H, d, J=5.0 Hz), 5.57 (1H, t,J=6.0 Hz), 7.03 (1H, dd, J=3.5, 8.5 Hz), 7.20 (2H, d, J=9.0 Hz), 7.26(1H, d, J=3.0 Hz), 7.64 (1H, d, J=8.5 Hz), 7.84 (2H, d, J=8.5 Hz).

Preparation of D

To the solution of C (2.7 g, 7.0 mmol) in dry DMF (50 ml) was added NaH(305 mg, 7.0 mmol, 55%) under Ar. The reaction mixture was stirred at 0°C. for 0.5 h, then (chloromethoxy)ethane (861 mg, 9.1 mmol) was added.The reaction mixture was stirred at ambient temperature for 1 h andquenched with i-PrOH. The solvent was evaporated under high vacuum. Theresidue was dissolved in EtOAc, washed with water. The organic layer wasseparated, dried (Na₂SO₄), filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:petroleum ether/EtOAc 5/1). The pure fraction was collected, and thesolvent was evaporated to afford D (2.5 g, 81%).

Preparation of E

A mixture of D (2.5 g, 5.64 mmol), bis(pinacolato)diboron (4.3 g, 16.9mmol), PdCl₂(dppf)₂ (184 mg, 0.226 mmol) and KOAc (1.65 g, 16.9 mmol) in1,4-dioxane (50 mL) was stirred at 80 overnight under Ar. The organiclayer was removed. The residue was purified by column chromatographyover silica gel (eluent: petroleum ether/EtOAc 5/1). The pure fractionwas collected, and the solvent was evaporated to afford E (2.7 g, 99%).

Preparation of compound D104

A mixture of E (2.7 g, 5.6 mmol) in 6 N HCl (20 mL) and THF (30 mL) wasstirred at ambient temperature overnight. The solvents were removed. Theresidue was purification by preparation HPLC to obtain the desiredcompound (1.3 g, 70%): ¹H NMR (DMSO-d₆, 500 MHz): δ 1.15 (3H, s), 1.16(3H, s), 3.38 (1H, m), 4.97 (2H, s), 7.13 (1H, dd, J=2.0, 8.0 Hz), 7.20(1H, d, J=5 Hz), 7.22 (2H, m), 7.80 (1H, d, J=8.0 Hz), 7.85 (2H, m),9.23 (1H, s).

19dh 5-(4-(ethylsulfonyl)phenoxy)benzo[c][1,2]oxaborol-1 (3H)-ol (D105)Preparation of B

To the solution of A (10.3 g, 48.1 mmol), 2-bromo-5-hydroxybenzaldehyde(6.0 g, 30 mmol), 4 A MS (25 g) and Cu(OAc)₂ (7.0 g, 39 mmol) in dryCH₂Cl₂ (200 ml) was added pyridine (4.22 g, 54 mmol) and Et₃N (7.5 ml,54 mmol) under Ar. The reaction mixture was stirred at ambienttemperature overnight and filtrated, washed with 2N HCl, extracted withCH₂Cl₂. The organic layer was separated, dried (Na₂SO₄), filtered, andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: petroleum ether/EtOAc 10/1 to4/1). The pure fraction was collected, and the solvent was evaporated toafford B (3.9 g, 35%): ¹H NMR (DMSO, 500 MHz): δ 10.18 (1H, S), 7.90(3H, m), 7.51 (1H, d, J=3.5 Hz), 7.46 (1H, dd, J=3.0 9.0 Hz), 7.27 (2H,d, J=8.5 Hz), 3.28 (2H, m), 1.11 (3H, t, J=7.5 Hz).

Preparation of C

To the solution of B (3.9 g, 10.6 mmol) in MeOH (250 ml) was added NaBH₄(200 mg, 5.3 mmol). The reaction mixture was stirred at ambienttemperature for 0.5 h. The solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: petroleumether/EtOAc 3/1). The pure fraction was collected, and the solvent wasevaporated to afford C (3.66 g, 93.4%): ¹H NMR (DMSO, 500 MHz): δ 1.10(3H, t, J=8.0 Hz), 3.26 (2H, m), 4.50 (2H, d, J=5.5 Hz), 5.54 (1H, t,J=6.0 Hz), 7.03 (1H, dd, J=3.0, 9.0 Hz), 7.20 (2H, m), 7.26 (1H, d,J=3.0 Hz), 7.65 (1H, d, J=8.5 Hz), 7.88 (2H, m).

Preparation of D

To the solution of C (3.66 g, 9.9 mmol) in dry DMF (50 ml) was added NaH(432 mg, 9.9 mmol, 55%) under Ar. The reaction mixture was stirred at 0°C. for 0.5 h, then (chloromethoxy)ethane (1.22 g, 13 mmol) was added.The reaction mixture was stirred at ambient temperature for 1 h andquenched with i-PrOH. The solvent was evaporated under high vacuum. Theresidue was dissolved in EtOAc, washed with water. The organic layer wasseparated, dried (Na₂SO₄), filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:petroleum ether/EtOAc 5/1). The pure fraction was collected, and thesolvent was evaporated to afford D (2.84 g, 67%): ¹H NMR (CDCl₃, 500MHz): δ 1.22 (3H, t, J=7.0 Hz), 1.29 (3H, t, J=7.0 Hz), 3.11 (2H, m),3.64 (2H, m), 4.65 (2H, s), 4.81 (2H, s), 6.89 (1H, d, J=8.5 Hz), 7.08(2H, d, J=8.0 Hz), 7.25 (1H, s), 7.57 (1H, d, J=8.5 Hz), 7.85 (2H, d,J=8.0 Hz).

Preparation of E

A mixture of D (2.84 g, 6.64 mmol), bis(pinacolato)diboron (5.08 g, 20mmol), PdCl₂(dppf)₂ (161 mg, 0.2 mmol) and KOAc (1.96 g, 20 mmol) in1,4-dioxane (50 mL) was stirred at 80 overnight under Ar. The organiclayer was removed. The residue was purified by column chromatographyover silica gel (eluent: petroleum ether/EtOAc 5/1). The pure fractionwas collected, and the solvent was evaporated to afford E (2.83 g, 90%).

Preparation of D105

A mixture of E (2.83 g, 5.94 mmol) in 6 N HCl (40 mL) and THF (60 mL)was stirred at ambient temperature overnight. The solvents were removed.The residue was purification by preparation HPLC to obtain the desiredcompound (1.0 g, 53%): ¹H NMR (CDCl₃, 500 MHz): δ 1.30 (3H, m), 3.12(2H, m), 5.08 (2H, s), 7.02 (1H, d, J=1.5 Hz), 7.07 (1H, dd, J=2.0, 7.5Hz), 7.12 (2H, m), 7.78 (1H, d, J=7.5 Hz), 7.87 (2H, m).

19di2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-6-(2-hydroxy-ethylamino)-nicotinonitrile(D106)

4-Bromo-3-[1,3]dioxolan-2-yl-phenol (2)

To a solution of 2-bromo-5-hydroxy-benzaldehyde (1) (10 g, 49.8 mmol) intoluene (200 mL) were added ethylene glycol (9.25 g, 149.3 mmol) andcatalytic amount of p-TsOH (200 mg). After attaching a Dean-Stark trap,the reaction was heated in a 136° C. oil batch for 3 hours. After thesolution was cooled to room temperature, it was washed with saturatedNaHCO₃ (200 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo to provide the 11.6 g (95% yield) of the titlecompound. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.40 (d, J=8.6 Hz, 1H),7.09 (d, J=3.1 Hz, 1H), 6.72 (dd, J=8.6, 3.1 Hz, 1H), 6.04 (s, 1H),4.18-4.04 (m, 4H).

6-(4-Bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile+2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile(4+5)

To a solution of 2,6-dichloro-nicotinonitrile (3) (7.06 g, 40.8 mmol) inacetonitrile (anhydrous, 300 mL) were added4-bromo-3-[1,3]dioxolan-2-yl-phenol (2) (10 g, 40.8 mmol) and K₂CO₃(5.63 g, 40.8 mmol). The reaction was heated at 65° C. for 3 hours. Thesolution was filtered and concentrated in vacuo to afford 15.6 g of theproduct mixture. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=9.0 Hz,2H), 7.62 (d, J=8.6 Hz, 2H), 7.46 (d, J=3.1 Hz, 1H), 7.41 (d, J=3.1 Hz,1H), 7.18-7.08 (m, 2H), 7.05 (dd, J=8.8, 2.9 Hz, 1H), 6.93 (d, J=8.2 Hz,1H), 6.11 (s, 1H), 6.09 (s, 1H), 4.19-3.99 (m, 8H).

2-(4-Bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-(2-hydroxy-ethylamino)-nicotinonitrile(6)

To a solution of6-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile and2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile, (4+5,2.5 g, 6.6 mmol) in acetonitrile (anhydrous, 50 mL) was added2-amino-ethanol (2) (3.96 g, 66 mmol). The reaction was heated at 80° C.for 2 hours. After the reaction cooled to room temperature, all volatilecomponents were removed in vacuo. Purification was accomplished bysilica gel chromatography, eluting with 25%-100% EtOAc/Hexane gradient,to give 1.1 g of title compound in 41% yield.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.57 (d, J=8.6 Hz, 2H), 7.45 (d,J=2.7 Hz, 1H), 7.06 (dd, J=8.8, 2.9 Hz, 1H), 6.09 (d, J=8.6 Hz, 1H),6.08 (s, 1H), 5.34 (br. s., 1H), 4.04-4.18 (m, 4H), 3.60 (t, J=5.3 Hz,2H), 3.28 (q, J=5.4 Hz, 2H).

2-(4-Bromo-3-formyl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile(7)

To a solution of 6(2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-(2-hydroxy-ethylamino)-nicotinonitrile,1.1 g, 2.7 mmol) in THF (200 mL) was added a HCl solution (1 M, 100 mL).The reaction was stirred at room temperature overnight. The THF wasevaporated in vacuo. The white solid that formed was filtered andair-dried to afford 0.94 g (55% yield for two steps) of the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.19 (s, 1H), 7.88 (br. s, 1H), 7.85(d, J=8.6 Hz, 1H), 7.72 (br. s., 1H), 7.65 (d, J=2.3 Hz, 1H), 7.52 (dd,J=8.8, 2.3 Hz, 1H), 6.34 (d, J=8.6 Hz, 1H), 4.61 (br. s., 1H), 3.40 (br.s, 2H), 3.05 (br. s, 2H)

2-(4-Bromo-3-formyl-phenoxy)-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-nicotinonitrile:(8)

To a solution of2-(4-bromo-3-formyl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile(7, 0.94 g, 2.59 mmol) in THF (anhydrous, 100 mL) were added tert-butylchloro-dimethyl silane (0.86 g, 5.7 mmol), Et₃N (0.8 mL, 5.7 mmol) andcat. amount of DMAP. The solution was stirred at room temperatureovernight. The solution was filtered and concentrated in vacuo.Purification was accomplished by silica gel chromatography, eluting with5%-50% EtOAc/hexanes gradient, to afford 1.1 g (89% yield) of the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.34 (s, 1H), 7.79 (d, J=2.7 Hz,1H), 7.66 (d, J=8.6 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.30 (dd, J=8.6,2.7 Hz, 1H), 6.14 (d, J=8.6 Hz, 1H), 5.23 (br. s., 1H), 3.64 (t, J=4.9Hz, 2H), 3.25 (q, J=5.4 Hz, 2H), 0.86 (s, 9H), 0.02 (s, 6H).

6-[2-(tert-Butyl-dimethyl-silanyloxy)-ethylamino]-2-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile:(9)

To a solution of2-(4-bromo-3-formyl-phenoxy)-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-nicotinonitrile(8, 1.1 g, 2.3 mmol) in 1,4-dioxane (anhydrous, 150 mL) were addedbispinacolatodiboron (0.71 g, 2.77 mmol), PdCl₂(dppf) (0.17 g, 0.23mmol) and KOAc (0.68 g, 6.9 mmol). The solution was stirred at r.t. withN₂ bubbling for 30 minutes. Then the reaction was heated at 100° C. for3 hours. The solution was filtered and concentrated in vacuo.Purification was accomplished by silica gel chromatography, eluting with5%-25% EtOAc/hexanes gradient to afford the mixture of the titlecompound (9) and de-brominated compound,6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-2-(3-formyl-phenoxy)-nicotinonitrile(10). The material was used directly in the next step without furtherpurification.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.62 (s, 1H), 10.02 (s, 1H), 7.94(d, J=8.20 Hz, 1H), 7.82 (d, J=1.95 Hz, 1H), 7.70-7.77 (m, 2H),7.53-7.64 (m, 4H), 7.37-7.50 (m, 3H), 6.12-6.19 (m, 2H), 5.27-5.37 (m,2H), 3.55-3.69 (m, 4H), 3.23 (m, 4H), 0.82-0.88 (m, 18H), 0.00 (d, 12H).

2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-6-(2-hydroxy-ethylamino)-nicotinonitrile:(D106)

To a clear solution of mixture of 9 and 10(6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-2-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrileand6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-2-(3-formyl-phenoxy)-nicotinonitrile)in MeOH (anhydrous, 200 mL) was slowly added NaBH₄ (0.26 g, 6.9 mmol).The reaction was stirred at room temperature for 4 hours, before theaddition of HCl solution (1 M, 30 mL). After overnight at roomtemperature, the solution was slowly evaporated in vacuo. Purificationwas accomplished by reverse phase Biotage with 5%-100% MeOH/H₂O gradientto afford 120 mg (29% yield) of the title compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.23 (s, 1H), 7.86-7.80 (m, 1H), 7.75(d, J=8.2 Hz, 1H), 7.70 (br. s., 1H), 7.22 (s, 1H), 7.14 (dd, J=8.0, 2.1Hz, 1H), 6.31 (d, J=8.6 Hz, 1H), 4.98 (s, 2H), 4.64 (br. s, 1H), 3.43(br. s, 2H), 3.07 (br. s, 2H); ES MS: m/z 312 (M+H)⁺; HPLC: 97.41% (220nm), 97.24 (MaxPlot).

19dj2-Ethoxy-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D107)

6-Chloro-2-ethoxy-nicotinamide (2)

Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide(1). Freshly prepared sodium ethoxide solution in ethanol (12.1 mL of2.17 M, 26.2 mmol) was slowly added over 10 min to a solution of 1 (5.01g, 26.2 mmol) in dimethylformamide (30 mL) at 15° C. [Note: a water bathwas used to maintain reaction temperature around 14-16° C.; sodiumethoxide was prepared from reaction of Na solid (1.50 g, 65.2 mmol) withanhydrous EtOH (30.0 mL)]. Upon completion of sodium ethoxide addition,the reaction was stirred for 40 min at 14-16° C. [Note: An aliquout (0.3mL) of reaction was concentrated. A ¹H NMR of aliquout recorded ind₆-DMSO showed 98% conversion to desired 2]. The reaction was pouredinto water (500 mL) and extracted with EtOAc (3×400 mL). All organicswere combined, dried over Na₂SO₄, filtered and concentrated to give thetitle compound as a light gray solid (5.20 g, 95% purity as establishedby ¹H NMR). The title compound was carried forward without furtherpurification. ¹H NMR 400 MHz (d₆-DMSO) δ8.16 (d, J=8.2 Hz, 1H), 7.76 (brs, 1H), 7.57 (br s, 1H), 7.17 (d, J=7.8 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H),1.35 (t, J=7.0 Hz, 3H).

6-Chloro-2-ethoxy-nicotinonitrile (3)

Experimental procedure for synthesis of6-chloro-2-ethoxy-nicotinonitrile (3) is the same as that described insynthesis of D46. The reaction of 6-chloro-2-morpholin-4-yl-nicotinamide(2) (5.20 g, 25.9 mmol) with phosphorus oxychloride (7.2 mL, 78 mmol)and pyridine (12.6 mL, 156 mmol) in acetonitrile (120 mL) gave a crudeblack oil upon workup. The black oil was fractionated by dry-pack columnchromatography as follows: the oil was diluted with CH₂Cl₂ (300 mL)followed by the addition of silica gel (40 g, 230-400 mesh) andconcentrated to dryness. This was loaded onto a silica column (120 g,230-400 mesh) and eluted with 5% EtOAc/hexanes. Pure fractions werecombined and concentrated to give the title compound as a white solid(4.20 g, 87% isolated). TLC eluted with 25% EtOAc/hexanes and renderedwith UV lamp gave R_(f)=0.8; ¹H NMR 400 MHz (CDCl₃) δ7.80 (d, J=7.8 Hz,1H), 6.99 (d, J=8.2 Hz, 1H), 4.51 (q, J=7.0 Hz, 2H), 1.45 (t, J=7.0 Hz,3H).

6-(4′-Bromo-3′-formyl-phenoxy)-2-ethoxy-nicotinonitrile (5)

Experimental procedure for synthesis of6-(4′-bromo-3′-formyl-phenoxy)-2-ethoxy-nicotinonitrile (5) is the sameas that described in synthesis of D46 except that the reaction washeated at 80° C. for 3.5 h. The reaction of6-chloro-2-ethoxy-nicotinonitrile (3) (3.52 g, 19.3 mmol),2-bromo-5-hydroxy-benzaldehyde (4) (2.58 g, 12.9 mmol) and K₂CO₃ (3.55g, 25.7 mmol) in DMF (40 mL) gave crude oil upon workup. The oil wasfractionated by dry-pack column chromatography as follows: the oil wasdiluted with CH₂Cl₂ (500 mL) followed by the addition of silica gel (80g, 230-400 mesh) and concentrated to dryness. This was loaded onto asilica column (120 g, 230-400 mesh) and eluted with gradient 10-30%EtOAc/hexanes. Pure fractions were combined and concentrated to give thetitle compound as a white solid (3.71 g, 61% isolated yield). TLC elutedtwice with 25% EtOAc/hexanes and rendered with UV lamp gave R_(f)=0.5;¹H NMR 400 MHz (CDCl₃) δ 10.35 (s, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.76 (d,J=3.1 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.29 (dd, J=8.6, 3.1 Hz), 6.57(d, J=8.2 Hz, 1H), 4.17 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.0 Hz, 3H).

2-Ethoxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(6)

Experimental procedure for synthesis of2-ethoxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(6) is the same as that described in synthesis of D46. The reaction of 6(3.62 g, 10.5 mmol), bis(pinacolato)diboron (7.97 g, 31.4 mmol) andpotassium acetate (3.08 g, 31.4 mmol) in a solvent mixture of dimethylformamide (20 mL) and 1,2-dimethoxyethane (80 mL) gave a brown oil uponworkup. The oil was fractionated by dry-pack column chromatography asfollows: the oil was diluted with CH₂Cl₂ (400 mL) followed by theaddition of silica gel (80 g, 230-400 mesh) and concentrated to dryness.This was loaded onto a silica column (80 g, 230-400 mesh) and elutedwith gradient 10-20% EtOAc/hexanes. The pure fractions were combined andconcentrated to give the title compound as a white solid (2.71 g, 74%isolated yield). TLC eluted with 25% EtOAc/hexanes and rendered with UVlamp gave R_(f)=0.4; ¹H NMR 400 MHz (CDCl₃) δ 10.64 (s, 1H), 7.97 (d,J=8.2 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.38 (dd,J=8.2, 2.3 Hz, 1H), 6.54 (d, J=8.2 Hz, 1H), 4.17 (q, J=7.0 Hz, 2H), 1.41(s, 12H), 1.28 (t, J=7.0 Hz, 3H).

2-Ethoxy-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D107)

Experimental procedure for synthesis of6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-morpholin-4-yl-nicotinonitrile(D107) is the same as that described in synthesis of (D46). The reactionof2-ethoxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(6) (2.71 g, 7.81 mmol) with NaBH₄ (886 mg, 23.4 mmol) gave an orangeoil containing D107 upon workup. The oil was fractionated by dry-packcolumn chromatography as follows: the oil was diluted with 30%MeOH/CH₂Cl₂ (400 mL) followed by the addition of silica gel (80 g,230-400 mesh) and concentrated to dryness. This was loaded onto a silicacolumn (160 g, 230-400 mesh) and eluted with 1:1:100 aceticacid:MeOH:CH₂Cl₂. The fractions containing D107 were collected andconcentrated to give a light yellow coloured oil. The oil was freezedried by first diluting with methanol (30 mL) followed by the additionof deionised water (400 mL), the resultant white suspension was frozenin a dry-ice acetone bath and placed overnight on freeze-dryer. A whitesolid of D107 was obtained (1.82 g, with 30 mol % pinacoldiol present asestablished by H NMR). To increase purity of D107, it was resubjected tocolumn chromatography and freeze-dried following the same conditions asbefore to give D107 (402 mg, 17% isolated yield) as a white solid. ¹HNMR 400 MHz (d₆-DMSO) δ9.25 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.79 (d,J=7.8 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.20 (dd, J=7.8, 2.0 Hz, 1H),6.69 (d, J=8.2 Hz, 1H), 4.99 (s, 2H), 4.17 (q, J=7.0 Hz, 2H), 1.21 (t,J=7.0 Hz, 3H); Mass Spectrum [M+H⁺]=297; HPLC purity 97.18% (Maxplot),97.65% (220 nm).

19dk2-hydroxy-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinonitrile(D108)

To a solution of 48% HBr (2 mL) and acetic acid (4 mL) was added6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-methoxynicotinonitrile(D46) (0.300 mg, 1.06 mmol). The reaction was stirred for 24 hours at50° C. Water was added and the mixture was extracted with ethyl acetate.The organic layer was washed with water, brine, dried over anhydroussodium sulfate, and then filtered. The solvent was removed under reducedpressure. The residue was purified by silica gel column (7:3 to 9:1ethyl acetate/hexane). The material was further purified by reversephase HPLC to give2-hydroxy-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinonitrile(0.027 g, 10% yield). ES(−) MS m/z=267 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆)δ ppm 4.97 (s, 2H), 6.4 (br s, 1H), 7.15 (d, J=7.9 Hz, 1H), 7.25 (s,1H), 7.77 (d, J=7.9 Hz, 1H), 8.09 (d, J=7.9 Hz, 1H), 9.24 (s, 1H), 12.7(br s, 1H).

19dl6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-4-methoxy-nicotinonitrile(D109)

6-Chloro-4-methoxy-nicotinonitrile (2)

To a solution of 4,6-dichloro-nicotinonitrile (1) (200 mg, 1.06 mmol) inmethanol (anhydrous, 10 mL) was added sodium methoxide solution (0.5M/MeOH, 2.12 mL, 1.06 mmol). The reaction was heated at 60° C.overnight. After cooling the reaction solution to room temperature, HCl(1M, 8 mL) was added. The volatile components were evaporated in vacuo.Purification was accomplished by Biotage (10%-50% EtOAc/hexanes gradientmobile phase) to afford 150 mg (77% yield) of the title compound. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 8.48 (s, 1H), 6.98 (s, 1H), 4.03 (s, 3H)

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-4-methoxy-nicotinonitrile(D109)

To a clear solution of 6-chloro-4-methoxy-nicotinonitrile (2) (200 mg,1.2 mmol) in DMF (anhydrous, 15 mL) were added3H-benzo[c][1,2]oxaborole-1,5-diol (3) (90 mg, 0.6 mmol) and Cs₂CO₃ (390mg, 1.2 mmol). The reaction was heated at 80° C. for 1.5 hours bymicrowave. HCl (1 M) was added till pH 2. All volatile components wereremoved in vacuo. Purification was accomplished by reverse phase Biotagewith 5%-100% MeOH/H₂O gradient to afford the 100 mg (30% yield) of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.32 (s, 1H), 8.40 (s,1H), 7.75 (d, J=7.8 Hz, 1H), 7.19 (s, 1H), 7.12-7.08 (m, 1H), 6.93 (s,1H), 4.96 (s, 2H), 3.99 (s, 3H); ES-MS m/z=283 (M+H)⁺; HPLC: 95.75% (220nm), 95.81% (MaxPlot).

19dm6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-methylamino-nicotinonitrile(D110)

6-Chloro-2-methylamino-nicotinamide (2)

Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide(1). A sealed reaction vessel containing 2,6-dichloro-nicotinamide (1)(6.23 g, 32.6 mmol) and methylamine (98 mL of 2M in THF, 196 mmol) inanhydrous dimethylformamide (60 mL) was heated to 60° C. for 4 h. Thereaction was then cooled to room temperature and diluted with water (800mL) and extracted with ethyl acetate (4×600 mL). All organics werecombined, dried over Na₂SO₄, filtered and concentrated to give a lightorange oil (7.10 g). The oil was diluted with CH₂Cl₂ (300 mL) followedby the addition of silica gel (50 g, 230-400 mesh) and concentrated todryness. This was loaded onto a silica column (200 g, 230-400 mesh) andeluted with gradient 30-50% EtOAc/hexanes. Pure fractions were combinedand concentrated to give the title compound as a white solid (4.73 g,78% isolated yield). TLC eluted with 50% EtOAc/hexanes and rendered withUV lamp gave R_(f)=0.5; ¹H NMR 400 MHz (CDCl₃) δ7.47 (d, J=8.5 Hz, 1H),7.90 (d, J=7.9 Hz, 1H), 1.48 (s, 3H).

6-Chloro-2-methylamino-nicotinonitrile (3)

Experimental procedure for synthesis of6-chloro-2-methylamino-nicotinonitrile (3) is the same as that describedin synthesis of D46. The reaction of 6-chloro-2-methylamino-nicotinamide(2) (4.70 g, 25.54 mmol) with phosphorus oxychloride (7.0 mL, 76.6 mmol)and pyridine (12.3 mL, 152 mmol) in acetonitrile (60 mL) at 60° C. for90 min gave crude black oil. The black oil was fractionated by dry-packcolumn chromatography as follows: the oil was diluted with CH₂Cl₂ (300mL) followed by the addition of silica gel (50 g, 230-400 mesh) andconcentrated to dryness. This was loaded onto a silica column (100 g,230-400 mesh) and eluted with 20% EtOAc/hexanes. Pure fractions werecombined and concentrated to give the titled compound as a white solid(2.91 g, 69% isolated yield). TLC eluted with 10% EtOAc/hexanes andrendered with UV lamp gave R_(f)=0.4; ¹H NMR 400 MHz (d₆-DMSO) δ7.91 (d,J=7.8 Hz, 1H), 7.52 (br q, J=4.7 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 2.80(d, J=4.7 Hz, 3H).

6-(4′-Bromo-3′-formyl-phenoxy)-2-methylamino-nicotinonitrile (5)

Experimental procedure for synthesis of6-(4′-bromo-3′-formyl-phenoxy)-2-methylamino-nicotinonitrile (5) is thesame as that described in synthesis of (D46) except that the reactionwas heated at 110° C. for 12 h. The reaction of6-Chloro-2-methylamino-nicotinonitrile (3) (1.90 g, 11.3 mmol),2-Bromo-5-hydroxy-benzaldehyde (4) (1.52 g, 7.56 mmol) and K₂CO₃ (2.09g, 15.1 mmol) in DMF (45 mL) gave crude oil upon workup. The oil wasfractionated by dry-pack column chromatography as follows: the oil wasdiluted with CH₂Cl₂ (400 mL) followed by the addition of silica gel (50g, 230-400 mesh) and concentrated to dryness. This was loaded onto asilica column (200 g, 230-400 mesh) and eluted with gradient 10-30%EtOAc/hexanes. Pure fractions were combined and concentrated to give thetitle compound as a white solid (1.42 g, 57% isolated yield). TLC elutedwith 10% EtOAc/hexanes and rendered with UV lamp gave R_(f)=0.2; ¹H NMR400 MHz (CDCl₃) δ 10.35 (s, 1H), 7.80 (d, J=2.7 Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.30 (dd, J=8.6, 3.1 Hz, 1H), 6.20 (d,J=8.2 Hz, 1H), 5.20 (br s, 1H), 2.80 (d, J=4.7 Hz, 1H).

6-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methylamino-nicotinonitrile(6)

Experimental procedure for synthesis of6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methylamino-nicotinonitrile(6) is the same as that described in synthesis of D46. The reaction of 6(1.40 g, 4.21 mmol), bis(pinacolato)diboron (3.21 g, 12.6 mmol) andpotassium acetate (1.24 g, 12.6 mmol) in a solvent mixture ofdimethylformamide (15 mL) and 1,2-dimethoxyethane (45 mL) gave a blackoil upon workup. The black oil was fractionated by dry-pack columnchromatography as follows: the oil was diluted with CH₂Cl₂ (400 mL)followed by the addition of silica gel (50 g, 230-400 mesh) andconcentrated to dryness. This was loaded onto a silica column (100 g,230-400 mesh) and eluted with gradient 10-40% EtOAc/hexanes. Purefractions were combined and concentrated to give the title compound as alight gray coloured solid (510 mg, 33% isolated yield). TLC with twoelutions of 25% EtOAc/hexanes and rendered with UV lamp gave R_(f)=0.3;¹H NMR 400 MHz (d₆-DMSO) δ 10.40 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.82(d, J=8.2 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.54 (dd, J=8.2, 2.3 Hz, 1H),7.32 (br q, J=4.3 Hz, 1H), 6.26 (d, J=8.6 Hz, 1H), 2.58 (d, J=4.3 Hz,3H), 1.35 (s, 12H).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-methylamino-nicotinonitrile(D110)

Experimental procedure for synthesis of6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-methylamino-nicotinonitrile(D110) is the same as that described in synthesis of (D46). The reactionof6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methylamino-nicotinonitrile(6) (490 mg, 1.35 mmol) with NaBH₄ (102 mg, 2.69 mmol) gave an orangeoil containing D110 upon workup. The oil was fractionated by dry-packcolumn chromatography as follows: the oil was diluted with CH₂Cl₂ (300mL) followed by the addition of silica gel (30 g, 230-400 mesh) andconcentrated to dryness. This was loaded onto a silica column (150 g,230-400 mesh) and eluted with 0.5:0.5:100 acetic acid:MeOH:CH₂Cl₂. Thefractions containing D110 were collected and concentrated to give alight yellow coloured oil. The oil was freeze dried by first dilutingwith methanol (50 mL) followed by the addition of deionised water (300mL), the resultant white suspension was frozen in a dry-ice acetone bathand placed overnight on freeze-dryer. A white solid of D110 was obtained(243 mg, 64% isolated yield). ¹H NMR 400 MHz (d₆-DMSO) δ9.20 (s, 1H),7.88 (d, J=8.2 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.25 (br s, 1H), 7.24(s, 1H), 7.15 (d, J=8.2 Hz, 1H), 6.13 (d, J=8.2 Hz, 1H), 4.98 (s, 2H),2.61 (d, J=4.3 Hz, 3H); Mass Spectrum [M+H]⁺=282; HPLC purity 94.93%(Maxplot), 93.43% (220 nm).

19dn6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-(2-methoxy-ethylamino)-nicotinonitrile(D111)

6-Chloro-2-(2-methoxy-ethylamino)-nicotinamide (2)

Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide(1). A sealed reaction vessel containing 2,6-dichloro-nicotinamide (1)(8.66 g, 45.3 mmol) and 2-methoxy-ethylamine (15.6 mL, 181 mmol) inanhydrous dimethylformamide (40 mL) was heated to 60° C. for 7 h. Thereaction was then cooled to room temperature. Dimethylformamide wasazeotropically removed by the addition and evaporation of toluene (6×700mL) by rotary evaporation with water bath at 70° C. An orange oil wasobtained (12.2 g). The oil was fractionated by dry-pack columnchromatography as follows: the oil was diluted with CH₂Cl₂ (400 mL)followed by the addition of silica gel (100 g, 230-400 mesh) andconcentrated to dryness. This was loaded onto a silica column (200 g,230-400 mesh) and eluted with 50% EtOAc/hexanes. Pure fractions werecombined and concentrated to give the title compound as a white solid(5.37 g, 64% isolated yield). ¹H NMR 400 MHz (d₆-DMSO) δ7.79 (d, J=7.8Hz, 1H), 7.30 (s, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 4.04 (br t,J=4.7 Hz, 1H), 3.80 (td, J=5.5, 4.7 Hz, 2H), 3.63 (t, J=5.5 Hz, 2H),2.94 (s, 3H).

6-Chloro-2-(2-methoxy-ethylamino)-nicotinonitrile (3)

Experimental procedure for synthesis of6-chloro-2-(2-methoxy-ethylamino)-nicotinonitrile (3) is the same asthat described in synthesis of (D46). The reaction of6-chloro-2-(2-methoxy-ethylamino)-nicotinamide (2) (6.85 g, 36.9 mmol)with phosphorus oxychloride (10.1 mL, 111 mmol) and pyridine (17.9 mL,221 mmol) in acetonitrile (90 mL) gave a black oil containing the titlecompound (6.97 g. 98% conversion) upon workup. The title compound wascarried forward without further purification. ¹H NMR 400 MHz (d₆-DMSO)δ7.94 (d, J=7.8 Hz, 1H), 7.50 (br s, 1H), 6.71 (d, J=8.2 Hz, 1H),3.54-3.43 (m, 4H), 3.26 (s, 3H).

6-(4′-Bromo-3′-formyl-phenoxy)-2-(2-methoxy-ethylamino)-nicotinonitrile(5)

Experimental procedure for synthesis of6-(4′-bromo-3′-formyl-phenoxy)-2-(2-methoxy-ethylamino)-nicotinonitrile(5) is the same as that described in synthesis of D46 except that thereaction was heated at 110° C. for 12 h. The reaction of6-chloro-2-(2-methoxy-ethylamino)-nicotinonitrile (3) (5.13 g, 24.2mmol), 2-bromo-5-hydroxy-benzaldehyde (4) (3.25 g, 16.2 mmol) and K₂CO₃(4.47 g, 32.3 mmol) in DMF (45 mL) gave crude oil of 5 upon workup. Theoil was fractionated by dry-pack column chromatography as follows: theoil was diluted with 10% MeOH/CH₂Cl₂ (300 mL) followed by the additionof silica gel (70 g, 230-400 mesh) and concentrated to dryness. This wasloaded onto a silica column (140 g, 230-400 mesh) and eluted withgradient 10-40% EtOAc/hexanes. Pure fractions were combined andconcentrated to give the title compound as a white solid (4.71 g, 52%isolated yield). TLC eluted with 25% EtOAc/hexanes and rendered with UVlamp gave R_(f)=0.3; ¹H NMR 400 MHz (CDCl₃) δ10.29 (s, 1H), 7.70 (d,J=3.0 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.23 (dd,J=8.6, 3.0 Hz, 1H), 6.17 (d, J=8.2 Hz, 1H), 5.57 (br s, 1H), 3.37-3.27(4H), 3.26 (s, 3H).

6-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-(2-methoxy-ethylamino)-nicotinonitrile(6)

Experimental procedure for synthesis of6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-(2-methoxy-ethylamino)-nicotinonitrile(6) is the same as that described in synthesis of (D46). The reaction of5 (4.70 g, 12.5 mmol), bis(pinacolato)diboron (6.35 g, 25.0 mmol) andpotassium acetate (2.45 g, 25.0 mmol) in 1,2-dimethoxyethane (120 mL)gave a brown oil. The brown oil was fractionated by dry-pack columnchromatography as follows: the oil was diluted with CH₂Cl₂ (400 mL)followed by the addition of silica gel (70 g, 230-400 mesh) andconcentrated to dryness. This was loaded onto a silica column (140 g,230-400 mesh) and eluted with gradient 10-20% EtOAc/hexanes. The purefractions were combined and concentrated to give the title compound as alight yellow solid (4.24 g, 80% isolated yield). ¹H NMR 400 MHz(d₆-DMSO) δ 10.38 (s, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.80 (d, J=8.2 Hz,1H), 7.66 (d, J=2.3 Hz, 1H), 7.50 (dd, J=8.2, 2.3 Hz, 1H), 7.29 (br s,1H), 6.29 (d, J=8.2 Hz, 1H), 3.32 (s, 3H), 3.17-3.13 (4H), 1.33 (s,12H).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-(2-methoxy-ethylamino)-nicotinonitrile(D111)

Experimental procedure for synthesis of6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-(2-methoxy-ethylamino)-nicotinonitrile(D111) is the same as that described in synthesis of (D46). The reactionof6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-(2-methoxy-ethylamino)-nicotinonitrile(6) (4.20 g, 9.92 mmol) with NaBH₄ (750 mg, 19.8 mmol) gave an orangeoil containing D111 upon workup. The oil was fractionated by dry-packcolumn chromatography as follows: the oil was diluted with 10%MeOH/CH₂Cl₂ (400 mL) followed by the addition of silica gel (70 g,230-400 mesh) and concentrated to dryness. This was loaded onto a silicacolumn (210 g, 230-400 mesh) and eluted with 1:1:100 aceticacid:MeOH:CH₂Cl₂. The fractions containing D111 were collected andconcentrated to give a light yellow coloured oil. The oil was freezedried by first diluting with acetonitrile (40 mL) followed by theaddition of deionised water (400 mL), the resultant white suspension wasfrozen in a dry-ice acetone bath and placed overnight on freeze-dryer. Awhite solid of D111 was obtained (1.70 g with 30 mol % pinacoldiol asdetermined by ¹H NMR). To increase purity of D111, it was re-subjectedto column chromatography and freeze-dried following the same conditionsas before to give D111 as a white solid (972 mg, 30% isolated yield). ¹HNMR 400 MHz (d₆-DMSO) δ9.21 (s, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.76 (d,J=7.8 Hz, 1H), 7.25 (br t, J=4.7 Hz, 1H), 7.24 (d, J=1.5 Hz, 1H), 7.14(dd, J=7.8, 1.5 Hz, 1H), 6.22 (d, J=8.6 Hz, 1H), 4.97 (s, 2H), 3.33 (s,3H), 3.25-3.15 (m, 4H); Mass Spectrum [M+H]⁺=324; HPLC purity 97.36%(Maxplot), 97.21% (220 nm), 96.44% (254 nm).

19do6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-methoxy-nicotinamide(D112)

6-(4-Bromo-3-formyl-phenoxy)-2-methoxy-nicotinamide (3)

A mixture of 6-chloro-2-methoxy-nicotinamide (7.15 g, 38.3 mmol),2-bromo-5-hydroxy-benzaldehyde (11.5 g, 57.5 mmol) and K₂CO₃ (15.9 g,115 mmol) in dimethylformamide (60 mL) was heated to 110° C. for 18hours. The reaction mixture was cooled to room temperature, diluted withH₂O (800 mL) and extracted with ethyl acetate (6×400 mL). The organicextracts were combined, dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica gel flash column chromatography(50-80% ethyl acetate/hexanes) to give the title compound as a lightbrown solid (5.19 g, 39% yield).

¹H NMR 400 MHz (d₆-DMSO) δ10.18 (s, 1H), 8.28 (d, J=8.2 Hz, 1H), 7.85(d, J=8.6 Hz, 1H), 7.68 (d, J=2.7 Hz, 1H), 7.59 (br s, 1H), 7.53 (dd,J=8.6, 2.7 Hz, 1H), 7.53 (br s, 1H), 6.72 (d, J=8.2 Hz, 1H), 3.71 (s,3H).

6-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methoxy-nicotinamide(4)

A suspension of 6-(4-bromo-3-formyl-phenoxy)-2-methoxy-nicotinamide(4.05 g, 11.5 mmol) in 1,2-dimethoxyethane (240 mL) was heated to 100°C. for 20 minutes until all solid dissolved. Bispinacolatodiboron (5.86g, 23.1 mmol) and KOAc (2.26 g, 23.1 mmol) were added and the reactionwas stirred at 100° C. for an additional 10 minutes. PdCl₂(dppf) (0.84g, 1.2 mmol) was added and the reaction mixture was stirred at 100° C.for 70 minutes. This was purified by silica gel flash columnchromatography (50-80% ethyl acetate/hexanes) to give the title compoundas a white solid (3.21 g, 69% yield).

¹H NMR 400 MHz (d₆-DMSO) δ 10.39 (s, 1H), 8.28 (d, J=8.2 Hz, 1H), 7.82(d, J=8.2 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.60 (br s, 1H), 7.53 (dd,J=8.2, 2.3 Hz, 1H), 7.53 (br s, 1H), 6.71 (d, J=8.2 Hz, 1H), 3.72 (s,3H), 1.33 (s, 12H).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-methoxy-nicotinamide(D112)

A solution of NaBH₄ (0.077 g, 2.0 mmol) in anhydrous methanol (10 mL)was added to a solution of6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methoxy-nicotinamide(2.51 g, 6.30 mmol) in CH₂Cl₂ (40 mL) and stirred at room temperaturefor 5 minutes. Solid NaBH₄ (0.400 g, 10.6 mmol) was then addedportionwise over 45 minutes at room temperature. The reaction wasstirred for an additional 30 minutes then quenched by the addition of50% aqueous acetic acid (1 mL). After stirring for an additional 30minutes at room temperature, the solution was concentrated in vacuo. Theresidue was purified by silica gel flash column chromatography(AcOH/MeOH/CH₂Cl₂ 1:3:100 v/v/v) to give the title compound as a whitefluffy solid (0.220 g, 12% yield).

¹H NMR 400 MHz (d₆-DMSO) δ9.20 (s, 1H), 8.25 (d, J=8.2 Hz, 1H), 7.76 (d,J=7.8 Hz, 1H), 7.58 (br s, 1H), 7.53 (br s, 1H), 7.25 (br s, 1H), 7.16(br d, J=7.8 Hz, 1H), 6.58 (d, J=8.2 Hz, 1H), 4.97 (s, 2H), 3.75 (s,3H).

Mass Spectrum [M+H⁺]=301.

HPLC purity 94.05% (Maxplot), 94.02% (220 nm), 92.23% (254 nm).

19dp2-(2-Benzyloxy-ethylamino)-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D113)

2-(2-Benzyloxy-ethylamino)-6-chloro-nicotinamide (3)

To a solution of 2,6-dichloro-nicotinamide (1) (12.6 g, 66.1 mmol) inacetonitrile (anhydrous, 200 mL) were added 2-benzyloxy-ethylamine (2)(10 g, 66.1 mmol) and triethylamine (11 mL, 79.3 mmol). The reaction washeated at 60° C. for 2 days. The solution was cooled to room temperatureand the suspension was filtered. The filtrate was evaporated in vacuo.The residue was purified by Biotage with 25%-100% EtOAc/hexanes toafford 15.8 g (78.3% yield) of the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.70 (br. s., 1H), 7.46 (d, J=8.2Hz, 1H), 7.40-7.23 (m, 5H), 6.44 (d, J=8.2 Hz, 1H), 5.97 (br. s., 2H),4.58 (s, 2H), 3.75-3.66 (m, 4H).

2-(2-Benzyloxy-ethylamino)-6-chloro-nicotinonitrile (4)

To a solution of 2-(2-benzyloxy-ethylamino)-6-chloro-nicotinamide (3,15.8 g, 51.7 mmol) in acetonitrile (anhydrous, 200 mL) were addedpyridine (33.4 mL, 413 mmol) and POCl₃ (18.9 mL, 207 mmol). The reactionwas heated at 55° C. for 3 hours. After cooling to room temperature,NaOH solution (10% aq.) was slowly added till pH 9. EtOAc (200 mL) wasadded and layers separated. The aqueous layer was extracted with EtOAc(2×200 mL). The combined organic layer was dried over MgSO₄, filtered,and evaporated in vacuo. Purification was accomplished by silica gelchromatography, eluting with 2%-20% EtOAc/hexanes gradient, to afford 10g (67% yield) of the title product.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.56 (d, J=7.8 Hz, 1H), 7.41-7.27(m, 5H), 6.60 (d, J=7.8 Hz, 1H), 5.68 (br. s., 1H), 4.57 (s, 2H),3.76-3.63 (m, 4H).

2-(2-Benzyloxy-ethylamino)-6-(4-bromo-3-formyl-phenoxy)-nicotinonitrile(6)

To a solution of2-(2-benzyloxy-ethylamino)-6-(4-bromo-3-formyl-phenoxy)-nicotinonitrile(4, 10 g, 34.7 mmol) in DMF (anhydrous, 300 mL) were added2-bromo-5-hydroxy-benzaldehyde (7 g, 34.7 mmol) and K₂CO₃ (9.6 g, 69.4mmol). The reaction was heated at 80° C. for 16 hours. DMF wasevaporated in vacuo. Purification was accomplished by silica gelchromatography, eluting with 2.5%-20% EtOAc/hexanes gradient, to afford10 g (64% yield) of the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.34 (s, 1H), 7.75-7.60 (m, 3H),7.39-7.20 (m, 6H), 6.20 (d, J=6.6 Hz, 1H), 5.59 (br s, 1H), 4.43 (s,2H), 3.50-3.36 (m, 4H).

2-(2-Benzyloxy-ethylamino)-6-[3-formyl-4-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(7)

To a solution of2-(2-benzyloxy-ethylamino)-6-(4-bromo-3-formyl-phenoxy)-nicotinonitrile(6, 10 g, 22.1 mmol) in 1,4-dioxane (anhydrous, 360 mL) were addedbispinacolatodiboron (6.74 g, 26.5 mmol), PdCl₂(dppf) (1.62 g, 2.21mmol) and KOAc (6.5 g, 66.3 mmol). The solution was stirred at r.t. withN₂ bubbling for 30 minutes. Then the reaction was heated at 100° C. for3 hours. After the reaction, the solution was filtered and concentratedin vacuo. Purification was accomplished by silica gel chromatography,eluting with 2.5%-20% EtOAc/hexanes gradient, to afford 9 g (82% yield)of the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.63 (s, 1H), 7.93 (d, J=8.2 Hz,1H), 7.77 (s, 1H), 7.66-7.62 (m, 1H), 7.38-7.25 (m, 6H), 6.18 (d, J=8.2Hz, 1H), 5.56 (br s, 1H), 4.48 (s, 2H), 3.47 (t, J=5.3 Hz, 2H), 3.39 (q,J=5.4 Hz, 2H), 1.39 (s, 12H).

2-(2-Benzyloxy-ethylamino)-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D113)

To a clear solution of2-(2-benzyloxy-ethylamino)-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(7, 9 g, 18 mmol) in MeOH (anhydrous, 200 mL) was slowly added NaBH₄(4.11 g, 108 mmol). The reaction was stirred at room temperature 4hours, before the addition of HCl solution (1 M, 200 mL). The stirringwas kept at room temperature overnight. Then the solution was slowlyevaporated in vacuo. The solid formed was filtered, washed with waterand air-dried to give 3.3 g (45.6% yield) of the title compound as awhite solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.91 (d, J=8.6 Hz, 2H), 7.76 (d, J=8.2Hz, 2H), 7.35-7.18 (m, 5H), 7.15 (s, 1H), 7.08 (dd, J=8.2, 2.0 Hz, 1H),6.23 (d, J=8.6 Hz, 1H), 4.94 (s, 2H), 4.29 (s, 2H), 3.34-3.21 (m, 4H);ES-MS: m/z 402 (M+H)⁺; HPLC: 92.59% (220 nm), 93.22% (MaxPlot).

19dq6-(4-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-methoxynicotinonitrile(D114)

A solution of anhydrous tetrahydrofuran (50 mL) and diisopropylamine (11mL) was cooled to 0° C. and had 1.6 M n-butyl lithium/hexanes (47 mL)added drop wise under nitrogen balloon. The mixture was stirred for 10minutes at 0° C. and was then cooled to −78° C. with an acetone dry icebath. A mixture of 4-bromo-2-fluoro-1-methoxybenzene (7.9 mL, 61 mmol)in anhydrous tetrahydrofuran (50 mL) was added drop wise, under nitrogenballoon, to the reaction. The mixture was then allowed to stir for 30minutes at −78° C. N,N-dimethylformamide (7.5 mL) was added drop wise at−78° C. under a nitrogen balloon. The reaction was stirred for 1 hour atroom temperature under a nitrogen balloon. Half of the solvent from thesolution was removed under reduced pressure and the solution wasextracted using ethyl acetate, water (300 mL), and 1 M HCl (65 mL). Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, and filtered. The solvent was removed under reduced pressure.The residue was crystallized by washing with hexanes. The solid wascollected via filtration and dried under reduced pressure to give6-bromo-2-fluoro-3-methoxybenzaldehyde (8.21 g, 58% yield).

A solution of 6-bromo-2-fluoro-3-methoxybenzaldehyde (2 g, 8.58 mmol) indichloromethane (43 mL) under a nitrogen balloon was cooled to −78° C.in an acetone dry ice bath. 1 M boron tribromide solution indichloromethane (9.5 mL) was added drop wise under nitrogen balloon. Thereaction was stirred at room temperature overnight. The reaction wasthen put on an ice water bath and the excess boron tribromide wasquenched with ice chips. Water was added and the solution was extractedwith dichloromethane. The aqueous layer was extracted two times withdichloromethane. The organic layers were combined, washed with brine,dried over anhydrous sodium sulfate, and filtered. The solvent wasremoved under reduced pressure to give6-bromo-2-fluoro-3-hydroxybenzaldehyde (1.61 g, 86% yield).

A solution of 6-bromo-2-fluoro-3-hydroxybenzaldehyde (1.61 g, 7.35mmol), ethylene glycol (2 mL, 36.8 mmol), para-toluenesulfonic acid(0.27 g, 0.147 mmol), and toluene (150 mL) was refluxed with adean-stark head for 16 hours. An aqueous solution of sodium bicarbonatewas added and the solution was extracted with ethyl acetate. The aqueouslayer was extracted five more times with ethyl acetate. The organiclayers were combined and washed with brine, dried over anhydrous sodiumsulfate, and filtered. The solvent was removed under reduced pressure togive 4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenol (1.81 g, 94% yield).

A solution of 6-chloro-2-methoxynicotinonitrile (1.16 g, 6.88 mmol),4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenol (1.81 g, 6.88 mmol),potassium carbonate (1.14 g, 8.26 mmol), and N,N-dimethylformamide (35mL) was stirred at 80° C. overnight. Water was added and the solutionwas extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, and filtered. The solventwas removed under reduced pressure and the residue was purified bysilica gel column using Combiflash to give6-(4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)-2-methoxynicotinonitrile(2.31 g, 85% yield).

To a solution of6-(4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)-2-methoxynicotinonitrile(2.31 g, 5.85 mmol) in 1,4-dioxane (30 mL) was added potassium acetate,bis(pinacolato)diboron (1.64 g, 6.44 mmol), and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.119 g,0.146 mmol). The reaction was stirred under nitrogen balloon at 80° C.overnight. The reaction was cooled to room temperature and filteredthrough Celite using ethyl acetate. The solvent was removed underreduced pressure. The residue was purified by silica gel column usingCombiflash to give6-(3-(1,3-dioxolan-2-yl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methoxynicotinonitrile(2.18 g, 85% yield).

A solution of6-(3-(1,3-dioxolan-2-yl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methoxynicotinonitrile(2.18 g, 4.93 mmol) in tetrahydrofuran (6 mL) was added 3 M HCl (3 mL).The solution was refluxed for four hours. The solution was cooled toroom temperature and water was added. The solution was extracted withethyl acetate. The organic layer was washed with water, then washed withbrine, dried over anhydrous sodium sulfate, and filtered. The solventwas removed under reduced pressure to give6-(2-fluoro-3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methoxynicotinonitrile(1.45 g, 74% yield).

A solution of6-(2-fluoro-3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methoxynicotinonitrile(1.45 g, 3.64 mmol) in methanol (15 mL) was put on an ice water bath.Sodium borohydride was added in portions. The reaction was stirred at 0°C. for five minutes and then stirred at room temperature for 2 hours.The reaction was cooled again to 0° C. on an ice water bath and sodiumborohydride (0.034 g, 0.91 mmol) was added. The reaction was stirred atroom temperature for 1 hour. The reaction was again cooled to 0° C. andsodium borohydride (0.034 g, 0.91 mmol) was again added. The reactionwas stirred at room temperature for one hour. The reaction wasneutralized to pH 6 to 7 using 1 M HCl. The solution was then extractedusing ethyl acetate and 0.5 M boronic acid solution in water. Theorganic layer was washed two more times with the 0.5 M boronic acidsolution, then washed with brine, dried over anhydrous sodium sulfate,and filtered. The solvent was removed under reduced pressure. Theresidue was purified by silica gel column using Combiflash to give6-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-methoxynicotinonitrile(0.220 g, 20% yield). ES(−) MS m/z=300 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 3.67 (s, 3H), 5.11 (s, 2H), 6.82 (d, J=8.2 Hz, 1H), 7.39 (t,J=6.8, J=7.5 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H),9.47 (s, 1H).

19dr6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile(D115)

4-Bromo-3-[1,3]dioxolan-2-yl-phenol (2)

To a solution of 2-bromo-5-hydroxy-benzaldehyde (1) (10 g, 49.8 mmol) intoluene (200 mL) were added ethylene glycol (9.25 g, 149.3 mmol) andcatalytic amount of p-TsOH (200 mg). After attaching a Dean-Stark trap,the reaction was heated at 136° C. for 3 hours. After the solution wascooled to room temperature, it was washed with saturated NaHCO₃ (200mL). The organic layer was dried over Na₂SO₄, filtered and evaporated invacuo to provide the 11.6 g (95% yield) of the title compound. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.40 (d, J=8.6 Hz, 1H), 7.09 (d, J=3.1 Hz,1H), 6.72 (dd, J=8.6, 3.1 Hz, 1H), 6.04 (s, 1H), 4.18-4.04 (m, 4H).

6-(4-Bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile+2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile(4+5)

To a solution of 2,6-dichloro-nicotinonitrile (3) (7.06 g, 40.8 mmol) inacetonitrile (anhydrous, 300 mL) were added4-bromo-3-[1,3]dioxolan-2-yl-phenol (2) (10 g, 40.8 mmol) and K₂CO₃(5.63 g, 40.8 mmol). The reaction was heated at 65° C. for 3 hours. Thesolution was filtered and evaporated in vacuo to afford 15.6 g of theproduct mixture. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=9.0 Hz,2H), 7.62 (d, J=8.6 Hz, 2H), 7.46 (d, J=3.1 Hz, 1H), 7.41 (d, J=3.1 Hz,1H), 7.18-7.08 (m, 2H), 7.05 (dd, J=8.8, 2.93 Hz, 1H), 6.93 (d, J=8.2Hz, 1H), 6.11 (s, 1H), 6.09 (s, 1H), 4.19-3.99 (m, 8H).

6-(4-Bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile(8)

To a solution of compound mixture,6-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile and2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile, (4+5,1 g, 2.6 mmol) in acetonitrile (anhydrous, 30 mL) was added2-methylamino-ethanol (6, 2.1 mL, 26 mmol). The reaction was heated at80° C. for 2 hours. After the reaction, all volatile components wereevaporated in vacuo. Purification was accomplished by silica gelchromatography, eluting with 10%-80% EtOAc/hexanes gradient, affording400 mg (36% yield) of the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.71-7.68 (m, 1H), 7.59 (d, J=8.6Hz, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.00 (dd, J=8.6, 3.0 Hz, 1H), 6.25 (d,J=8.6 Hz, 1H), 6.06 (s, 1H), 4.19-4.04 (m, 4H), 3.60-3.43 (m, 4H),3.35-3.30 (m, 3H).

2-(4-Bromo-3-formyl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile(9)

To a solution of6-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile(8, 7.6 g, 18.1 mmol) in THF (100 mL) was added HCl solution (1 M, 100mL). The reaction was stirred at 50° C. overnight. After the reaction,all THF was evaporated in vacuo. The aqueous solution was extracted withEtOAc (2×50 mL). The organic layer was washed with water (3×50 mL),dried over MgSO₄, filtered and evaporated in vacuo to afford 6.8 g (100%yield) of the desired product.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.34 (s, 1H), 7.80-7.65 (m, 3H),7.26-7.22 (m, 1H), 6.28 (d, J=8.6 Hz, 1H), 3.71-3.64 (m, 2H), 3.58 (t,J=5.7 Hz, 2H), 3.29 (s, 3H), 2.03 (s, 1H).

6-(4-Bromo-3-formyl-phenoxy)-2-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-nicotinonitrile(10)

To a solution of2-(4-bromo-3-formyl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile(9, 8 g, 21.3 mmol) in THF (anhydrous, 100 mL) were added TBDMS-Cl (3.21g, 21.3 mmol) and Et₃N (3 mL, 21.3 mmol). The solution was stirred atroom temperature for 2 days. The solution was filtered and concentratedin vacuo. Purification was accomplished by silica gel chromatography,eluting with 5%-50% EtOAc/hexanes gradient, to afford 10 g (85% yield)of the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.37 (s, 1H), 7.78-7.73 (m, 2H),7.69 (d, J=8.6 Hz, 1H), 7.30-7.26 (m, 1H), 6.28 (d, J=8.6 Hz, 1H),3.66-3.57 (m, 4H), 3.28 (s, 3H), 0.87 (s, 9H), 0.00 (s, 6H).

2-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile:(11)

To a solution of6-(4-bromo-3-formyl-phenoxy)-2-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-nicotinonitrile(10, 5 g, 10.2 mmol) in 1,4-dioxane (anhydrous, 150 mL) were addedbispinacolatodiboron (3.11 g, 12.2 mmol), PdCl₂(dppf) (0.75 g, 1.02mmol) and KOAc (3 g, 30.6 mmol). The solution was stirred at r.t. withN₂ bubbling for 30 minutes. Then the reaction was heated at 100° C. for3 hours. The solution was filtered and concentrated in vacuo.Purification was accomplished by silica gel chromatography, eluting with5%-10% EtOAc/hexanes gradient to afford 5.2 g (95% yield) of the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.70 (s, 1H), 7.98 (d, J=8.2 Hz,1H), 7.81 (d, J=2.3 Hz, 1H), 7.77-7.73 (m, 1H), 7.39 (dd, J=8.2, 2.3 Hz,1H), 6.28 (d, J=8.2 Hz, 1H), 3.71-3.51 (m, 4H), 3.29 (s, 3H), 1.44 (s,12H), 0.87 (s, 9H), 0.00 (s, 6H).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile:(D115)

To a clear solution of 11 (5.2 g, 9.7 mmol) in MeOH (anhydrous, 150 mL)was slowly added NaBH₄ (2.2 g, 58 mmol). The reaction was stirred atroom temperature for 4 hours, before the addition of HCl solution (1 M,150 mL). The stirring was kept at room temperature overnight. Then thesolution was slowly evaporated in vacuo. Purification was accomplishedby reverse phase Biotage with 5%-100% MeOH/H₂O gradient to afford 786 mg(25% yield) of the desired product as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.22 (s, 1H), 7.93 (d, J=8.6 Hz, 1H),7.75 (d, J=8.2 Hz, 1H), 7.22 (s, 1H), 7.13 (dd, J=7.8, 2.0 Hz, 1H), 6.31(d, J=8.6 Hz, 1H), 4.98 (s, 2H), 4.66 (t, J=5.1 Hz, 1H), 3.48-3.44 (m,2H), 3.41 (t, J=5.1 Hz, 2H), 3.16 (s, 3H); ES MS: m/z 326 (M+H)⁺; HPLC:99.0% (220 nm), 98.21% (MaxPlot).

19ds2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-4-methoxy-pyrimidine-5-carbonitrile(D116)

2-Chloro-4-methoxy-pyrimidine-5-carbonitrile (2)

To a solution of 2,4-dichloro-pyrimidine-5-carbonitrile (1) (300 mg,1.72 mmol) in THF (anhydrous, 20 mL) was added sodium methoxide solution(0.5 M/MeOH, 3.45 mL, 1.72 mmol). The reaction was stirred at r.t. for30 minutes. The volatile components were removed in vacuo. Purificationwas accomplished by Biotage silica gel chromatography (2%-30%EtOAc/hexanes gradient) to give 130 mg (45% yield) of the titlecompound. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.62 (s, 1H), 4.18 (s,3H)

2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-4-methoxy-pyrimidine-5-carbonitrile

To a clear solution of 2-chloro-4-methoxy-pyrimidine-5-carbonitrile (2)(500 mg, 2.95 mmol) in DMF (anhydrous, 30 mL) were added3H-benzo[c][1,2]oxaborole-1,5-diol (3) (221 mg, 1.47 mmol) and Cs₂CO₃(1054 mg, 3.24 mmol). The reaction was heated at 80° C. for 2 h bymicrowave. HCl (1 M) was added till pH 2. All volatile components wereremoved in vacuo. Purification was accomplished by reverse phase Biotagewith 5%-100% MeOH/H₂O gradient to afford the 125 mg (30% yield) of thetitle compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.26 (s, 1H), 8.88 (s, 1H), 7.80 (d,J=8.0 Hz, 1H), 7.31 (s, 1H), 7.23 (dd, J=8.0, 1.8 Hz, 1H), 5.01 (s, 2H),4.00 (s, 3H); ES-MS m/z=284 (M+H)⁺; HPLC: 92.78% (220 nm), 94.74%(MaxPlot).

19dt5-[5-Aminomethyl-6-(2-benzyloxy-ethylamino)-pyridin-2-yloxy]-3H-benzo[c][1,2]oxaborol-1-ol(D117)

To a solution of (D113) (2.5 g, 6.23 mmol) in MeOH (anhydrous, 500 mL)was added Pd/C (100 mg). The hydrogenation was carried out at roomtemperature, under H₂ (50 Psi) for 30 minutes. Then the suspension wasfiltered. The filtrate was concentrated in vacuo. Purification wasaccomplished by silica gel chromatography, eluting with 5%-20% MeOH/DCMgradient, to afford 1.95 g (99% yield) of the title compound as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.18 (br. s., 3H), 7.74 (d, J=8.2 Hz,1H), 7.54 (d, J=7.8 Hz, 1H), 7.10 (s, 1H), 7.06-7.01 (m, 1H), 6.09 (d,J=7.8 Hz, 1H), 4.96 (s, 2H), 3.94-3.88 (m, 3H), 3.41 (t, J=6.1 Hz, 2H),3.17 (t, J=6.1 Hz, 2H); ES-MS: m/z 316 (M+H)⁺; HPLC: 96.08% (220 nm),95.90% (MaxPlot).

19du6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile(D118) and 19dv6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-4-(2-hydroxy-ethoxy)-nicotinonitrile(D119)

6-Chloro-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (2)

To a solution of 2-(tetrahydro-pyran-2-yloxy)-ethanol (6.32 g, 43.30mmol) in DMF (15 mL) at 0° C. was added sodium hydride (95% in mineraloil, 1.09 g, 43.30 mmol) portion-wise. After 1 h at room temperature,this mixture was slowly added to a solution of4,6-dichloro-nicotinonitrile (5.0 g, 28.90 mmol) in DMF (25 mL) at 0° C.After overnight, DMF was removed under reduced pressure, and theresulting mixture was diluted with EtOAc (50 mL). The organic layer waswashed with water (20 mL) and brine (3×20 mL) solution, dried overanhydrous Na₂SO₄, filtered, and concentrated. Purification wasaccomplished by flash chromatography on silica gel using 5-25%EtOAc/hexanes gradient elution to yield the title compound (4.9 g, 60%)as a transparent oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.47 (s, 1H), 7.10(s, 1H), 4.70 (t, J=3.3 Hz, 1H), 4.32-4.45 (m, 2H), 4.19-4.08 (m, 1H),3.91-3.80 (m, 2H), 3.59-3.50 (m, 1H), 1.83-1.68 (m, 2H), 1.65-1.50 (m,4H).

6-(4-Bromo-3-formyl-phenoxy)-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile(3)

To a mixture of6-chloro-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (4.8 g,16.62 mmol) and 2-bromo-5-hydroxy-benzaldehyde (4.01 g, 19.94 mmol) inDMF (30 mL) was added potassium carbonate (3.44 g, 24.93 mmol). Theresulting mixture was heated at 80° C. overnight. DMF was removed underreduced pressure and the residue was diluted with EtOAc (200 mL). Theorganic layer was washed with water (20 mL) and brine (3×20 mL), driedover Na₂SO₄, filtered, and concentrated to give white solid.Purification was accomplished by flash chromatography on silica gelusing 2-25% EtOAc/hexanes as gradient elution yielding the titlecompound (4.8 g, 64%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.19 (s, 1H), 8.46 (s, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.60 (d, J=2.7 Hz,1H), 7.49 (dd, J=8.6, 2.7 Hz, 1H), 7.09 (s, 1H), 4.75-4.67 (m, 1H),4.49-4.45 (m, 2H), 4.00-3.89 (m, 1H), 3.85-3.74 (m, 2H), 3.49-3.41 (m,1H), 1.78-1.53 (m, 2H), 1.39-1.53 (m, 4H).

6-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile(4)

To a degassed solution of6-(4-bromo-3-formyl-phenoxy)-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile(4.9 g, 10.09 mmol) in 1,4-dioxane (35 mL) was addedbis(pinacolato)diboron (3.18 g, 12.54 mmol), potassium acetate (3.21 g,37.7 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride (0.38 g,0.52 mmol). After purging with N₂ again, the suspension was heated at80° C. for 3 h. The mixture was cooled to room temperature and passedthrough Celite® and diluted with EtOAc (150 mL). The organic layer waswashed with water (20 mL) and brine (20 mL) solution, dried over Na₂SO₄,filtered, and concentrated. Purification was accomplished by flashchromatography on silica gel using 5-25% EtOAc/hexanes gradient elutionyielding the title compound (3.8 g, 64%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.39 (s, 1H), 8.44 (s, 1H), 7.83 (d, J=7.8 Hz, 1H),7.62 (d, J=2.3 Hz, 1H), 7.49 (dd, J=8.2, 2.3 Hz, 1H), 7.06 (s, 1H), 4.69(s, 1H), 4.47-4.39 (m, 2H), 4.02-3.92 (m, 1H), 3.80-3.70 (m, 2H),3.49-3.38 (m, 1H), 1.72-1.58 (m, 2H), 1.50-1.42 (m, 4H), 1.33 (s, 12H).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile(D118)

To a solution of6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile(0.5 g, 1.02 mmol) in methanol (3 mL) at 0° C. was added sodiumborohydride (0.07 g, 2.04 mmol). After 1 h at room temperature, thesolution was cooled in an ice bath and 1M NaHSO₄ (2.6 mL, 2.6 mmol) wasadded until pH reached to 4˜5. The resulting mixture was sonicated andstirred at 0° C. for 1 h. The white solid that separated was filtered,washed with MeOH and lyophilized to yield the title compound D118 (0.1g, 25%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.22 (s, 1H),8.46 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.15-7.09(m, 1H), 7.02 (s, 1H), 4.99 (s, 2H), 4.71 (s, 1H), 4.49-4.40 (m, 2H),4.02-3.91 (m, 1H), 3.84-3.73 (m, 2H), 3.49-3.41 (m, 1H), 1.72-1.58 (m,2H), 1.55-1.41 (m, 4H); MS (ES) m/z: 397 (M+1)⁺; HPLC purity 97.55%(Maxplot), 97.65% (220 nm).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-4-(2-hydroxy-ethoxy)-nicotinonitrile(D119)

To a suspension of6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile(1.8 g, 4.54 mmol) in methanol (15 mL) at 0° C. was added 1M HCl inether (5.45 ml, 5.45 mmol) and left at the same temperature for 2 h. Thesolid that formed was collected by filtration and dissolved in minimumvolume of 10% MeOH/CHCl₃ and passed through a short column. The solventwas evaporated to yield the title compound (D119) (0.28 g, 20%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.23 (s, 1H), 8.45 (s, 1H),7.77 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.15-7.09 (m, 1H), 7.01 (s, 1H),5.04 (t, J=5.3 Hz, 1H), 4.99 (s, 2H), 4.30 (t, J=4.5 Hz, 2H), 3.79-3.76(m, 2H); MS (ES) m/z: 313 (M+1)⁺; HPLC purity 99.27% (Maxplot), 99.66%(220 nm). Elemental analysis for C₁₅H₁₃BN₂O₅: Calculated C, 57.73; H,4.20; N, 8.98. found C, 57.53; H, 4.31; N, 8.95.

19dw4-Ethoxy-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D120)

4,6-Dichloro-nicotinamide (2)

Oxalyl chloride (7.70 mL, 88.3 mmol) was added over 1 hour to asuspension of 4,6-dichloronicotinic acid (8.47 g, 44.1 mmol) indimethylformamide (200 mL) at room temperature. The reaction mixture wasstirred for an additional 3 hours at room temperature then concentratedin vacuo. The residue was dissolved in CH₂Cl₂ (200 mL) followed by thedropwise addition of NH₄OH (8.3 mL, 130 mmol) over 30 minutes [Note:reaction is exothermic upon addition of NH₄OH and care was taken tocontrol the rate of addition so that the reaction temperature did notexceed 25° C.]. The reaction mixture was stirred for an additional 1hour at room temperature then diluted with water (600 mL) and extractedwith EtOAc (4×600 mL). The organic extracts were combined, dried overNa₂SO₄, filtered and concentrated to give the title compound as a lightbrown solid (8.05 g, 95% yield). This material was carried forwardwithout further purification.

¹H NMR 400 MHz (d₆-DMSO) δ 8.48 (s, 1H), 8.10 (br s, 1H), 7.87 (br s,2H).

4,6-Dichloro-nicotinonitrile (3)

Pyridine (20.3 mL, 250 mmol) was added to a suspension of4,6-dichloro-nicotinamide (8.00 g, 41.9 mmol) in acetonitrile (180 mL)at room temperature POCl₃ (11.7 mL, 126 mmol) was added over 3 minutesat room temperature. The reaction mixture was heated at 60° C. with for1.5 hours. The reaction solution was cooled to room temperature andpoured into aqueous NaOH (0.8M, 600 mL) followed by extraction withEtOAc (6×400 mL). The organic extracts were combined, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gel flashcolumn chromatography (30% ethyl acetate/hexanes) to give the titlecompound as a light orange solid (6.41 g, 88%)

¹H NMR 400 MHz (CDCl₃) δ8.67 (s, 1H), 7.58 (s, 1H).

6-Chloro-4-ethoxy-nicotinonitrile (4)

A solution of NaOEt in ethanol (1.93M, 18.8 mL, 36.3 mmol) was addedover 10 minutes to a solution of 4,6-dichloro-nicotinonitrile (6.29 g,36.3 mmol) in dimethylformamide (60 mL) at room temperature. Thereaction was stirred for 3 hours, diluted with water (600 mL) andextracted with EtOAc (4×400 mL). The organic extracts were combined,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby silica gel flash column chromatography (20% ethyl acetate/hexanes) togive the title compound as a white solid (3.82 g, 58%) and4-chloro-6-ethoxy-nicotinonitrile (0.41 g, 6.0%) as a white solid.

6-Chloro-4-ethoxy-nicotinonitrile (4): ¹H NMR 400 MHz (CDCl₃) δ8.47 (s,1H), 6.93 (s, 1H), 4.24 (q, J=7.0 Hz, 2H), 1.54 (t, J=7.0 Hz, 3H).

4-Chloro-6-ethoxy-nicotinonitrile (5): ¹H NMR 400 MHz (CDCl₃) δ 8.43 (s,1H), 6.87 (s, 1H), 4.44 (q, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H).

6-(4-Bromo-3-formyl-phenoxy)-4-ethoxy-nicotinonitrile (7)

A mixture of 6-chloro-4-ethoxy-nicotinonitrile (3.80 g, 20.8 mmol),2-bromo-5-hydroxy-benzaldehyde (4.60 g, 22.9 mmol) and K₂CO₃ (4.31 g,31.2 mmol) in dimethyl formamide (30 mL) was heated to 110° C. for 5hours. The reaction mixture was diluted with H₂O (400 mL) and extractedwith ethyl acetate (8×400 mL). The organic extracts were combined, driedover Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel flash column chromatography (15-50% ethyl acetate/hexanes) togive the title compound as a white solid (5.31 g, 73%).

¹H NMR 400 MHz (CDCl₃) δ 10.34 (s, 1H), 8.22 (s, 1H), 7.71 (d, J=8.6 Hz,1H), 7.68 (d, J=3.1 Hz, 1H), 7.27 (dd, J=8.6, 3.1 Hz, 1H), 6.50 (s, 1H),4.24 (q, J=7.0 Hz, 2H), 1.55 (t, J=7.0 Hz, 3H).

4-Ethoxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(8)

A mixture of 6-(4-bromo-3-formyl-phenoxy)-4-ethoxy-nicotinonitrile (5.30g, 15.3 mmol), bispinacolatodiboron (7.75 g, 30.5 mmol) and KOAc (3.00g, 30.5 mmol) in 1,2-dimethoxyethane (180 mL) was heated to 110° C. for10 minutes. PdCl₂(dppf) (0.56 g, 0.76 mmol) was added and the reactionmixture was stirred vigorously at 110° C. for 1.5 hours. This waspurified by silica gel flash column chromatography (20-40% ethylacetate/hexanes) to give the title compound as a white solid (3.53 g,59% yield).

¹H NMR 400 MHz (CDCl₃) δ 10.68 (s, 1H), 8.23 (s, 1H), 8.01 (d, J=8.2 Hz,1H), 7.73 (d, J=2.3 Hz, 1H), 7.36 (dd, J=8.2, 2.3 Hz, 1H), 6.49 (s, 1H),4.23 (q, J=7.0 Hz, 2H), 1.54 (t, J=7.0 Hz, 3H), 1.39 (s, 12H).

4-Ethoxy-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D120)

A solution of NaBH₄ (0.10 g, 2.6 mmol) in anhydrous methanol (20 mL) wasadded to a solution of4-ethoxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(3.53 g, 8.95 mmol) in CH₂Cl₂ (80 mL) and stirred at room temperaturefor 5 minutes. Solid NaBH₄ (0.58 g, 15.3 mmol) was then addedportionwise over 30 minutes at room temperature. The reaction mixturewas stirred for an additional 30 minutes, quenched by the addition 70%aqueous acetic acid (3 mL) then stirred for an additional 1 hour at roomtemperature. The reaction was concentrated and the residue purified bysilica gel flash column chromatography (AcOH/MeOH/CH₂Cl₂ 1:1:100 v/v/v)to give the title compound as a viscous oil. The oil was lyophilized togive a white solid (0.781 g, 29% yield).

¹H NMR 400 MHz (d₆-DMSO) δ9.24 (s, 1H), 8.45 (s, 1H), 7.77 (d, J=8.2 Hz,1H), 7.22 (s, 1H), 7.13 (dd, J=7.8, 1.6 Hz, 1H), 6.97 (s, 1H), 4.99 (s,2H), 4.32 (q, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H).

Mass Spectrum [M+H⁺]=297.

HPLC purity 96.58% (Maxplot), 98.13% (220 nm), 97.49% (254 nm).

19dx2-Benzylamino-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D121)

2-Benzylamino-6-chloro-nicotinamide (3)

To a solution of 2,6-dichloro-nicotinamide (1) (2.3 g, 12.2 mmol) inacetonitrile (anhydrous, 100 mL) were added 2-benzylamine (2) (1.3 g,12.2 mmol) and triethylamine (1.7 mL, 12.2 mmol). The reaction washeated at 60° C. for 4 hours. The solution was cooled to roomtemperature and filtered. The filtrate was evaporated in vacuo.Purification was achieved by Biotage silica gel chromatography with5%-50% EtOAc/hexanes gradient to afford 1.71 g (54% yield) of the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.82 (br. s., 1H), 7.52 (d, J=8.2Hz, 1H), 7.40-7.23 (m, 6H), 6.50 (d, J=8.2 Hz, 1H), 5.66 (br. s., 2H),4.70 (d, J=5.5 Hz, 2H).

2-Benzylamino-6-chloro-nicotinonitrile (4)

To a solution of 2-benzylamino-6-chloro-nicotinamide (3, 1.71 g, 6.6mmol) in acetonitrile (anhydrous, 80 mL) were added pyridine (4.26 mL,52.7 mmol) and POCl₃ (2.41 mL, 264 mmol). The reaction was heated at 55°C. for 3 hours. After cooling to room temperature, NaOH solution (10%aq., 30 mL) was slowly added till pH 9. EtOAc (200 mL) was added and thelayers separated. The aqueous layer was extracted with EtOAc (2×200 mL).The combined organic layer was dried over MgSO₄, filtered, andevaporated in vacuo. Purification was accomplished by silica gelchromatography, eluting with 2%-20% EtOAc/hexanes gradient, to afford0.66 g (42% yield) of the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=8.2 Hz, 1H), 7.39-7.29(m, 5H), 6.65 (d, J=7.8 Hz, 1H), 5.55 (br. s., 1H), 4.69 (d, J=5.5 Hz,2H)

2-Benzylamino-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D121)

To a clear solution of 2-benzylamino-6-chloro-nicotinonitrile (4, 660mg, 2.73 mmol) in DMF (anhydrous, 30 mL) were added3H-benzo[c][1,2]oxaborole-1,5-diol (3) (205 mg, 1.37 mmol) and Cs₂CO₃(880 mg, 2.73 mmol). The reaction was heated at 80° C. for 1.5 hours bymicrowave. HCl (1 M) was added till pH 2. All volatile components wereremoved in vacuo. Purification was accomplished by reverse phase Biotagewith 10%-90% MeOH/H₂O gradient to afford the 480 mg (49.5% yield) of thetitle compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.25 (s, 1H), 8.00-7.95 (m, 1H), 7.91(d, J=8.2 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.20-7.05 (m, 5H), 6.87 (dd,J=7.4, 1.9 Hz, 1H), 6.25 (d, J=8.6 Hz, 1H), 4.93 (s, 2H), 4.17 (d, J=5.8Hz, 2H), 3.32 (s, 1H); ES-MS: m/z 358 (M+H)⁺; HPLC: 97.8% (220 nm),97.61% (MaxPlot).

19dy6-(6-Fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-methoxynicotinonitrile(D122)

A solution of 4-fluoro-3-methoxybenzaldehyde (4.3 g, 27.9 mmol),potassium bromide (16.6 g, 139.5 mmol), bromine (3.6 mL, 69.8 mmol), andwater (45 mL) were stirred at room temperature for 24 hours. Morebromine (1.43 mL, 27.9 mmol) was added and the reaction was stirred atroom temperature overnight. The product precipitated out of solution andwas collected via filtration and dried under reduced pressure to give2-bromo-4-fluoro-5-methoxybenzaldehyde (6.01 g, 92% yield).

A solution of 2-bromo-4-fluoro-5-methoxybenzaldehyde (1.19 g, 8.20mmol), 48% HBr (57 mL) and glacier acetic acid (57 mL) were refluxed at130° C. for 5 hours. The glacier acetic acid was removed under reducedpressure. The solution was neutralized using sodium carbonate. Water wasadded and the mixture was extracted using ethyl acetate. The organiclayer was washed with brine, dried over anhydrous sodium sulfate, andfiltered. The solvent was removed under reduced pressure. The residuewas purified by silica gel column using Combiflash to give2-bromo-4-fluoro-5-hydroxybenzaldehyde (1.15 g, 64% yield).

The rest of the steps are identical to those of6-(4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-methoxynicotinonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.67 (s, 3H), 4.98 (s, 2H), 6.82 (d,J=8.4 Hz, 1H), 7.48 (d, J=6.6 Hz, 1H), 7.62 (d, J=9.8 Hz, 1H), 8.27 (d,J=8.4 Hz, 1H), 9.35 (s, 1H).

19dz5-Hydroxy-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D123)

5-Hydroxy-nicotinonitrile (2)

A mixture of 5-bromo-pyridin-3-ol (9.94 mL, 54.0 mmol) and CuCN (7.4 g,82.62 mmol) in DMF (20 mL) was heated at 135° C. for 5 hour. DMF wasremoved under reduced pressure, the residue was diluted with NH₄OH (10mL) at 0° C. The mixture was bubbled with ammonia gas for 1 hour, cooledto 0° C. and acidified with conc. HCl (35 mL) until pH reached to 4. Theresulting mixture was extracted with EtOAc (5×100 mL). The organic layerwas washed with water (2×100 mL) and brine (2×100 mL) solution, driedover anhydrous Na₂SO₄, filtered, and concentrated to give yellow solid.Purification was accomplished by flash chromatography on silica gelusing 5-25% EtOAc/hexanes gradient elution to yield the title compound(2.5 g, 39%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.78(s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.41 (d, J=2.7 Hz, 1H), 7.61-7.57 (m,1H).

6-Chloro-5-hydroxy-nicotinonitrile (3)

A mixture of 5-hydroxy-nicotinonitrile (2.0 g, 16.66 mmol), andN-chlorosuccinimide (3.3 g, 25.0 mmol) in acetonitrile (33 mL) washeated in a sealed tube at 107° C. overnight. Acetonitrile was removedunder reduced pressure, the residue was diluted with EtOAc (100 mL). Theorganic layer was washed with water (10 mL) and brine (2×10 mL), driedover Na₂SO₄, filtered, and concentrated to give brown oil. Purificationwas accomplished by flash chromatography on silica gel using 20-80%EtOAc/hexanes gradient elution to yield the title compound (0.55 g, 36%)as a yellow solid ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.70 (s, 1H), 8.35(d, J=2.0 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H); MS (ES) m/z: 153 (M−1)⁻.

6-Chloro-5-methoxymethoxy-nicotinonitrile (4)

To a solution of 6-chloro-5-hydroxy-nicotinonitrile (1.12 g, 7.24 mmol)in DCM (15 mL) was added N,N-diisopropyl ethylamine (1.57 mL, 9.05 mmol)followed by the addition of chloro-methyl methylether (0.66 mL, 8.69mmol) slowly at 0° C. After overnight at room temperature, the reactionmixture was washed with saturated NaHCO₃ (10 mL) and brine (10 mL),dried over Na₂SO₄, filtered, and concentrated to give yellow oil.Purification was accomplished by flash chromatography on silica gelusing 5-25% EtOAc/hexanes gradient elution to yield the title compound(0.68 g, 50%) as a transparent oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.53(d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 5.42 (s, 2H), 3.40 (s, 3H);MS (ES) m/z: 199 (M+1)⁺.

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-5-methoxymethoxy-nicotinonitrile(6)

To a mixture of 6-chloro-5-methoxymethoxy-nicotinonitrile (0.68 g, 3.42mmol) and 3H-benzo[c][1,2]oxaborole-1,5-diol (0.56 g, 3.76 mmol) in DMF(10 mL) was added cesium carbonate (2.45 g, 7.52 mmol). The resultingsuspension was heated at 80° C. for overnight. DMF was removed underreduced pressure, the residue was diluted with EtOAc (50 mL), washedwith water (10 mL) and brine (10 mL), dried over Na₂SO₄, filtered, andconcentrated to give brown oil. Purification was accomplished by flashchromatography on silica gel using 1-100% MeOH/EtOAc gradient elution toyield the title compound (0.40 g, 40%) as a transparent oil. ¹H NMR (400MHz, DMSO-d₆) δ ppm 9.23 (s, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.77 (d,J=8.6 Hz, 1H), 7.23 (s, 1H), 7.14 (d, J=7.4 Hz, 1H), 5.40 (s, 2H), 4.98(s, 2H), 3.45 (s, 3H); MS (ES) m/z: 313 (M+1)⁺.

5-Hydroxy-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D123)

To a suspension of6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-5-methoxymethoxy-nicotinonitrile(0.28 g, 0.89 mmol) in methanol (4 mL) was added 1 M HCl in ether (1.79mL, 1.79 mmol) at 0° C. The reaction was heated at 65° C. for 2 hours.Methanol was removed under reduced pressure and the product was purifiedby reverse phase prep HPLC using CH₃CN/H₂O (0.1% AcOH) as the eluent toyield the title compound (0.10 g, 41%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 9.22 (s, 1H), 8.02 (s, 1H), 7.76 (d, J=7.8 Hz, 1H),7.57 (s, 1H), 7.19 (s, 1H), 7.15-7.09 (m, 1H), 4.98 (s, 2H); MS (ES)m/z: 267 (M−1)⁻; HPLC purity 92.91% (Maxplot), 92.41% (220 nm).

19ea2-Ethoxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile(D124)

A solution of2-hydroxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile(0.200 g, 0.749 mmol), iodoethane (0.182 mL, 2.25 mmol) andN,N-dimethylformamide (10 mL) under nitrogen balloon was put on an icewater bath. Sodium hydride (0.090 g, 2.25 mmol) was added and themixture was stirred under nitrogen balloon at 0° C. for 15 minutes. Thereaction was then stirred at room temperature for 2 hours. Water wasadded to quench the excess sodium hydride and the mixture was thenneutralized using 1 M HCl. Water was added and the solution wasextracted using ethyl acetate. The organic layer was washed with water,brine, dried over anhydrous sodium sulfate, and filtered. The solventwas removed under reduced pressure. The residue was solidified by addingisopropylether. The precipitate was filtered and dried under reducedpressure to give2-ethoxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile(0.131 g, 59% yield). ES(−) MS m/z=294 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.33 (t, J=6.9 Hz, 3H), 4.13 (q, J=7.0 Hz, 2H), 4.95 (s, 2H), 6.56(dd, J=8.6, 1.9 Hz, 1H), 6.89 (d, J=1.9 Hz, 1H), 7.08 (dd, J=8.1, 1.6Hz, 1H), 7.14 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H),9.19 (s, 1H).

19eb6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-(2,2,2-trifluoro-ethoxy)-nicotinonitrile(D125)

6-Chloro-2-(2,2,2-trifluoro-ethoxy)-nicotinamide (3)

To a solution of 2,2,2-trifluoro-ethanol (2) (4.8 mL, 67.8 mmol) wasadded sodium (0.52 g, 22.6 mmol). The reaction was kept O/N. Then to thesolution was added 2,6-dichloro-nicotinamide (1, 4.32 g, 22.6 mmol) inDMF (30 mL). The reaction was kept at r.t. for 3 h. The suspension wasfiltered. The filtrate was concentrated in vacuo. Purification wasaccomplished by Biotage silica gel chromatography with 10%-60%EtOAc/hexanes gradient to afford 4.68 g (81% yield) of the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.54 (d, J=7.8 Hz, 1H), 7.29 (br.s., 1H), 7.21 (d, J=7.8 Hz, 1H), 5.91 (br. s., 1H), 4.93-4.89 (m, 2H).

6-Chloro-2-(2,2,2-trifluoro-ethoxy)-nicotinonitrile (4)

To a solution of 6-chloro-2-(2,2,2-trifluoro-ethoxy)-nicotinamide (3,4.68 g, 18.3 mmol) in acetonitrile (anhydrous, 100 mL) were addedpyridine (11.86 mL, 146.8 mmol) and POCl₃ (6.72 mL, 73.4 mmol). Thereaction was heated at 55° C. for 3 hours. After cooling to roomtemperature, NaOH solution (10% aq.) was slowly added till pH 9. EtOAc(200 mL) was added and layers separated. The aqueous layer was extractedwith EtOAc (2×200 mL). The combined organic layer was dried over MgSO₄,filtered, and concentrated in vacuo. The purification was accomplishedby silica gel chromatography, eluting with 2%-20% EtOAc/hexanesgradient, to afford 4 g (92% yield) of the titled product.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.92 (d, J=7.9 Hz, 1H), 7.17 (d,J=7.9 Hz, 1H), 4.92-4.84 (m, 2H).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-(2,2,2-trifluoro-ethoxy)-nicotinonitrile(D125)

To a solution of 6-chloro-2-(2,2,2-trifluoro-ethoxy)-nicotinonitrile (4,1.26 g, 5.33 mmol) in DMF (anhydrous, 30 mL) were added3H-benzo[c][1,2]oxaborole-1,5-diol (400 mg, 2.67 mmol) and Cs₂CO₃ (1.91g, 5.87 mmol). The reaction was heated at 80° C. for 2 h by microwave.After the reaction cooled to room temperature, HCl (1 M, 20 mL) wasadded. The volatiles were removed in vacuo. Purification wasaccomplished by preparative HPLC, eluting with 5%-90% ACN/watergradient, to afford 380 mg (41% yield) of the title compound as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.28 (s, 1H), 8.36 (d, J=8.2 Hz, 1H),7.81 (d, J=7.8 Hz, 1H), 7.31 (s, 1H), 7.23 (dd, J=8.2, 2.0 Hz, 1H), 6.83(d, J=8.2 Hz, 1H), 5.00 (s, 2H), 4.90-4.83 (m, 2H); ¹F NMR (376 MHz,DMSO-d₆) ppm −72.84; ES MS: m/z 351 (M+H)⁺; HPLC: 96.35% (220 nm),97.02% (MaxPlot). Elemental analysis for C₁₅H₁₀BF₃N₂O₄, Calculated: C,51.47%; H, 2.88%; N, 8.00%. Found: C, 51.44%; H, 2.86%; N, 8.30%.

19ec2-[3-cyano-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-pyridin-2-yloxy]-ethylacetate (D126)

Acetic acid2-[3-cyano-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-pyridin-2-yloxy]-ethylester (D126)

Refer to (D99) for the synthesis of D126, which was isolated as aby-product during the reverse phase preparative HPLC purification ofD99. A gradient mixture of CH₃CN/H₂O (0.1% AcOH) was used as the eluentto yield D126 (0.25 g, 20%), which was obtained as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 9.24 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.77 (d,J=8.2 Hz, 1H), 7.26 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 6.71 (d, J=8.2 Hz,1H), 4.98 (s, 2H), 4.35-4.26 (m, 2H), 4.22-4.13 (m, 2H), 1.98 (s, 3H);¹³C NMR (400 MHz, DMSO-d₆) δ ppm 170.86, 164.58, 163.75, 156.71, 155.37,147.67, 132.62, 120.87, 115.95, 114.86, 104.43, 89.54, 70.34, 65.92,62.27, 21.22 (boron substituted C not observed); MS (ES) m/z: 355(M+1)⁺; HPLC purity 96.66% (Maxplot), 97.43% (220 nm). Elementalanalysis for C₁₇H₁₅BN₂O₆: Calculated C=57.66%, H=4.27%, N=7.91%. FoundC=57.58%, H=4.41%, N=7.71%.

19ed2-(2,2-Difluoro-ethoxy)-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D127)

6-Chloro-2-(2,2-difluoro-ethoxy)-nicotinamide (2)

2,2-Difluoroethanol (3.51 mL, 55.5 mmol) was added dropwise over 30minutes to a suspension of NaH (2.22 g, 60% w/w dispersion in oil) in1,2-dimethoxyethane (40.0 mL) at 14° C. and stirred for 1 hour. Aportion of this solution (25 mL, 35 mmol) was added dropwise over 10minutes to a solution of 2,6-dichloro-nicotinamide (5.30 g, 27.7 mmol)in dimethylformamide (40 mL) at 14° C. The resultant suspension wasstirred for an additional 1 hour at 14° C., diluted with water (600 mL)and extracted with EtOAc (3×400 mL). The organic extracts were combined,dried over Na₂SO₄, filtered and concentrated to give title compound as alight orange solid (6.39 g, 97%). This was used without furtherpurification.

¹H NMR 400 MHz (d₆-DMSO) δ8.19 (d, J=7.8 Hz, 1H), 7.87 (br s, 1H), 7.53(br s, 1H), 7.28 (d, J=7.8 Hz, 1H), 6.47 (tt, J=54.7, 3.5 Hz, 1H), 4.66(td, J=11.3, 3.5 Hz, 2H).

6-Chloro-2-(2,2-difluoro-ethoxy)-nicotinonitrile (3)

POCl₃ (7.5 mL, 81 mmol) was added to a solution of6-chloro-2-(2,2-difluoro-ethoxy)-nicotinamide (6.39 g, 27.0 mmol) inacetonitrile (100 mL) at 14° C. over 5 minutes. The reaction mixture washeated to 60° C. for 1.5 hours then cooled to room temperature. Themixture was poured into an ice cold solution of aqueous NaOH (0.6M, 800mL) and extracted with EtOAc (4×800 mL). The organic extracts werecombined, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel flash column chromatography (20% ethylacetate/hexanes) to give the title compound as a light yellow oil whichsolidified upon standing (5.10 g, 86%).

¹H NMR 400 MHz (CDCl₃) δ7.89 (d, J=8.2 Hz, 1H), 7.12 (d, J=8.2 Hz, 1H),6.17 (tt, J=55.1, 3.5 Hz, 1H), 4.66 (td, J=13.3, 3.5 Hz, 2H).

6-(4-Bromo-3-formyl-phenoxy)-2-(2,2-difluoro-ethoxy)-nicotinonitrile (5)

A mixture of 6-chloro-2-(2,2-difluoro-ethoxy)-nicotinonitrile (5.01 g,22.9 mmol), 2-bromo-5-hydroxy-benzaldehyde (3.84 g, 19.1 mmol) and K₂CO₃(5.3 g, 38 mmol) in dimethylformamide (30 mL) was heated to 110° C. for3 hours. The reaction mixture was cooled to room temperature, dilutedwith H₂O (800 mL) and extracted with ethyl acetate (4×800 mL). Theorganic extracts were combined, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel flash columnchromatography (20% ethyl acetate/hexanes) to give the title compound asa white solid (6.62 g, 90%)

¹H NMR 400 MHz (CDCl₃) δ 10.36 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.74 (d,J=3.1 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.28 (dd, J=8.6, 3.1 Hz, 1H),6.70 (d, J=8.2 Hz, 1H), 5.97 (tt, J=54.7, 4.3 Hz, 1H), 4.31 (td, J=13.3,4.3 Hz, 2H).

2-(2,2-Difluoro-ethoxy)-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(6)

A mixture of6-(4-bromo-3-formyl-phenoxy)-2-(2,2-difluoro-ethoxy)-nicotinonitrile(6.60 g, 17.2 mmol), bispinacolatodiboron (8.75 g, 34.5 mmol) and KOAc(3.38 g, 34.5 mmol) in 1,2-dimethoxyethane (180 mL) was heated to 110°C. for 10 minutes. PdCl₂(dppf) (0.630 g, 0.86 mmol) was added and thereaction mixture was stirred at 110° C. for 2 hours. This was purifiedby silica gel flash column chromatography (10-40% ethyl acetate/hexanes)to give the title compound as a light grey solid (5.22 g, 70% yield).

¹H NMR 400 MHz (d₆-DMSO) δ 10.39 (s, 1H), 8.37 (d, J=8.6 Hz, 1H), 7.84(d, J=8.2 Hz, 1H), 7.77 (d, J=2.7 Hz, 1H), 7.61 (dd, J=8.2, 2.3 Hz, 1H),6.93 (d, J=8.2 Hz, 1H), 6.27 (tt, 54.3, 3.5 Hz, 1H), 4.39 (td, J=14.9,3.5 Hz, 2H), 1.36 (s, 12H).

2-(2,2-Difluoro-ethoxy)-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D127)

A solution of NaBH₄ (0.100 g, 2.6 mmol) in anhydrous methanol (20 mL)was added to a solution of2-(2,2-difluoro-ethoxy)-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(5.20 g, 12.1 mmol) in CH₂Cl₂ (80 mL) and stirred at room temperaturefor 5 minutes. Solid NaBH₄ (0.815 g, 21.5 mmol) was then addedportionwise over 30 minutes to the reaction at room temperature and thereaction stirred for an additional 30 minutes. The reaction was quenchedby the addition of 60% aqueous acetic acid (5 mL), stirred for 30minutes at room temperature then concentrated in vacuo. The residue waspurified by silica gel flash column chromatography (AcOH/MeOH/CH₂Cl₂1:1:100 v/v/v) to give the title compound as a viscous oil which waslyophilized to give a white solid (1.92 g, 48% yield).

¹H NMR 400 MHz (d₆-DMSO) δ9.27 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 7.78 (d,J=7.9 Hz, 1H), 7.29 (d, J=1.5 Hz, 1H), 7.20 (dd, J=7.9, 1.5 Hz, 1H),6.79 (d, J=8.2 Hz, 1H), 6.25 (tt, J=54.5, 3.5 Hz, 1H), 4.97 (s, 2H),4.40 (td, J=11.4, 3.5 Hz, 2H).

Mass Spectrum [M+H⁺]=333.

HPLC purity 98.15% (Maxplot), 97.48% (220 nm), 97.44% (254 nm).

19ee6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-isopropoxy-nicotinonitrile(D128)

6-Chloro-2-isopropoxy-nicotinamide (2)

To a solution of propan-2-ol (2.94 mL, 39.26 mmol) in DMF (15 mL) at 0°C. was added sodium hydride (95% in mineral oil, 0.94 g, 39.26 mmol) inportions and stirred for 1 h at room temperature. This mixture wasslowly added to a solution of 2,6-dichloro-nicotinamide (5.0 g, 26.17mmol) in DMF (25 mL) at 0° C. The reaction mixture was stirred at roomtemperature overnight. DMF was removed under reduced pressure, and theresulting mixture was diluted with EtOAc (50 mL), washed with water(2×20 mL) and brine (2×10 mL) solution, dried over anhydrous Na₂SO₄,filtered, and concentrated to give yellow oil. Purification wasaccomplished by flash chromatography on silica gel using 5-50%EtOAc/hexanes gradient elution to yield the title compound (2.94 g, 64%)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.45 (d, J=8.2 Hz, 1H),7.73 (br. s., 1H), 7.03 (d, J=7.8 Hz, 1H), 5.84 (br. s., 1H), 5.64-5.47(m, 1H), 1.45 (d, J=6.3 Hz, 6H).

6-Chloro-2-isopropoxy-nicotinonitrile (3)

To a solution of 6-chloro-2-isopropoxy-nicotinamide (2.87 g, 13.37 mmol)and pyridine (6.48 mL, 80.22 mmol) in acetonitrile (25 mL) was addedphosphorus oxychloride (3.68 mL, 40.13 mmol) over a period of 5 min. Thereaction was stirred at 55° C. for 1 h. Acetonitrile was evaporated invacuo and the resulting residue was neutralized with 1N NaOH at 0° C.until pH reached to 7. The reaction mixture was extracted with EtOAc(100 mL). The organic layer was collected and the aqueous layer wasfurther extracted with EtOAc (3×50 mL). All organics were combinedwashed with brine (2×25 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated to give yellow oil. Purification was accomplished by flashchromatography on silica gel using 5-25% EtOAc/hexanes gradient elutionto yield the title compound (2.1 g, 81%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.28 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H),5.34-5.20 (m, 1H), 1.33 (d, J=6.2 Hz, 6H).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-isopropoxy-nicotinonitrile(D128)

To a mixture of 6-chloro-2-isopropoxy-nicotinonitrile (0.73 g, 4.0 mmol)and 3H-Benzo[c][1,2]oxaborole-1,5-diol (0.40 g, 2.66 mmol) in DMF (10mL) was added potassium carbonate (1.10 g, 7.98 mmol). The resultingsuspension was heated at 80° C. overnight. DMF was removed under reducedpressure, the residue was diluted with EtOAc (50 mL), washed with water(10 mL) and brine (2×10 mL), dried over Na₂SO₄, filtered, andconcentrated to give brown oil. Purification was accomplished by reversephase preparative HPLC using MeOH/H₂O (0.1% AcOH) as the eluent to yieldthe title compound (0.21 g, 21%) as white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.27 (s, 1H), 8.23 (d, J=8.6 Hz, 1H), 7.79 (d, J=7.8 Hz,1H), 7.29 (s, 1H), 7.22-7.14 (m, 1H), 6.70 (d, J=8.2 Hz, 1H), 4.99 (s,2H), 4.85 (sept., J=6.3 Hz, 1H), 1.19 (d, J=6.3 Hz, 6H); MS (ES) m/z:311 (M+1); HPLC purity 98.44% (Maxplot), 97.99% (220 nm).

19ef2-tert-butylamino-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D129) and 19eg2-amino-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D130)

2-tert-Butylamino-6-chloro-nicotinamide (3)

To a solution of 2,6-dichloro-nicotinamide (1) (4 g, 20.9 mmol) inacetonitrile (anhydrous, 60 mL) were added tert-butylamine (2) (13.28mL, 12.6 mmol) and triethylamine (15.7 mL, 12.6 mmol). The reaction washeated at 80° C. for 2 days. The solution was cooled to room temperatureand the resulting suspension was filtered. The filtrate was concentratedin vacuo. The residue was purified by Biotage silica gel chromatographywith 20%-100% EtOAc/hexanes gradient elution to afford 850 mg (18%yield) of the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.51 (br. s., 1H), 7.47 (d, J=7.8Hz, 1H), 6.42 (d, J=7.8 Hz, 1H), 5.65 (br. s., 2H), 1.48 (s, 9H).

2-tert-Butylamino-6-chloro-nicotinonitrile (4)

To a solution of 2-tert-butylamino-6-chloro-nicotinamide (3, 850 mg,3.73 mmol) in acetonitrile (anhydrous, 40 mL) were added pyridine (2.42mL, 29.9 mmol) and POCl₃ (1.37 mL, 14.9 mmol). The reaction was heatedat 55° C. for 3 hours. After cooling to room temperature, NaOH solution(10% aq.) was slowly added till pH 9. The solution was extracted withEtOAc (3×50 mL). The combined organic layer was dried over MgSO₄,filtered, and concentrated in vacuo. Purification was accomplished byBiotage silica gel chromatography, eluting with 2%-30% EtOAc/hexanesgradient, to afford 630 mg (80% yield) of the title product.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52 (d, J=7.9 Hz, 1H), 6.56 (d,J=7.9 Hz, 1H), 5.15 (br. s., 1H), 1.49 (s, 9H).

6-(4-Bromo-3-formyl-phenoxy)-2-tert-butylamino-nicotinonitrile (6)

To a solution of 2-tert-butylamino-6-chloro-nicotinonitrile (4, 630 mg,3 mmol) in DMF (100 mL) were added 2-bromo-5-hydroxy-benzaldehyde (603mg, 3 mmol) and K₂CO₃ (828 mg, 6 mmol). The reaction was heated at 80°C. for 24 h. After cooling to r.t., DMF was removed in vacuo.Purification was accomplished by Biotage silica gel chromatography witha 2.5%-10% EtOAc/hexanes gradient to afford 950 mg (85% yield) of thetitle compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.34 (s, 1H), 7.71-7.67 (m, 2H),7.62 (d, J=8.2 Hz, 1H), 7.24 (dd, J=8.6, 2.8 Hz, 1H), 6.24 (d, J=8.2 Hz,1H), 5.04 (s, 1H), 1.12 (s, 9H)

2-tert-Butylamino-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(7)

To a solution of6-(4-bromo-3-formyl-phenoxy)-2-tert-butylamino-nicotinonitrile (6, 950mg, 2.54 mmol) in 1,4-dioxane (anhydrous, 100 mL) were addedbispinacolatodiboron (0.775 g, 3.05 mmol), PdCl₂(dppf) (0.19 g, 0.25mmol) and KOAc (0.75 g, 7.62 mmol). The solution was stirred at r.t.with N₂ bubbling for 30 minutes, then heated at 100° C. for 3 hours. Thesolution was filtered and concentrated in vacuo. Purification wasaccomplished by silica gel chromatography, eluting with 5%-30%EtOAc/hexanes gradient, producing 1 g (93.5%) of the title compound (7).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.63 (s, 1H), 7.96 (d, J=8.2 Hz,1H), 7.74 (d, J=2.2 Hz, 1H), 7.63-7.60 (m, 1H), 7.34 (dd, J=8.1, 2.1 Hz,1H), 6.22 (d, J=8.2 Hz, 1H), 5.03 (br. s., 1H), 1.40 (s, 12H), 1.17 (s,9H).

2-tert-butylamino-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D129)

To a solution of2-tert-butylamino-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(7, 1 g, 2.38 mmol) in DMF (anhydrous, 100 mL) was added NaBH₄ (0.55 g,14.25 mmol). The reaction was kept at r.t. for 4 h, before the additionof HCl (1 M, 30 mL). The reaction was kept O/N. All the volatilecomponents were removed in vacuo. Purification was accomplished bypreparative HPLC, eluting with 5%-80% ACN/water gradient, to afford 430mg (56% yield) of the title compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.21 (s, 1H), 7.88 (d, J=8.2 Hz, 1H),7.74 (d, J=8.2 Hz, 1H), 7.19 (s, 1H), 7.09 (dd, J=7.8, 1.9 Hz, 1H), 6.31(d, J=8.2 Hz, 1H), 5.94 (s, 1H), 4.93 (s, 2H), 1.03 (s, 9H); ES MS: m/z324 (M+H)⁺; HPLC: 96.97% (220 nm), 96.71% (MaxPlot).

2-amino-6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D130)

A solution of (D129) (400 mg, 1.23 mmol) in TFA (25 mL) was heated at70° C. for 3 h. All volatile components were removed in vacuo.Purification was accomplished by preparative HPLC with 5%-90% ACN/watergradient to afford 78 mg (24% yield) of the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.23 (s, 1H), 7.88 (d, J=8.6 Hz, 1H),7.76 (d, J=8.2 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.12-7.09 (m, 1H), 6.98(s, 2H), 6.19 (d, J=8.2 Hz, 1H), 4.98 (s, 2H); ES MS: m/z 268 (M+H)⁺;HPLC: 96.36% (220 nm), 97.08% (MaxPlot).

19eh6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-propoxy-nicotinonitrile(D131)

6-Chloro-2-propoxy-nicotinamide (2)

To a solution of propan-1-ol (2.94 mL, 39.26 mmol) in DMF (15 mL) at 0°C. was added sodium hydride (95% in mineral oil, 0.94 g, 39.26 mmol) inportions and stirred for 1 h at room temperature. This mixture wasslowly added to a solution of 2,6-dichloro-nicotinamide (5.0 g, 26.17mmol) in DMF (25 mL) at 0° C. The reaction mixture was stirred at roomtemperature overnight. DMF was removed under reduced pressure, and theresulting mixture was diluted with EtOAc (60 mL), washed with water(2×20 mL) and brine (2×10 mL) solution, dried over anhydrous Na₂SO₄,filtered, and concentrated to give yellow oil. Purification wasaccomplished by flash chromatography on silica gel using 5-60%EtOAc/hexanes gradient elution to yield the title compound (3.8 g, 68%)as a transparent oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.46 (d, J=8.2 Hz,1H), 7.69 (br. s., 1H), 7.06 (d, J=8.2 Hz, 1H), 5.86 (br. s., 1H), 4.48(t, J=6.6 Hz, 2H), 1.99-1.79 (m, 2H), 1.07 (t, J=7.4 Hz, 3H).

6-Chloro-2-propoxy-nicotinonitrile (3)

To a solution of 6-chloro-2-propoxy-nicotinamide (3.80 g, 17.71 mmol)and pyridine (8.50 mL, 106.21 mmol) in acetonitrile (25 mL) was addedphosphorus oxychloride (4.81 mL, 53.13 mmol) over a period of 5 min. Thereaction was stirred at 55° C. for 1 h. Acetonitrile was evaporated invacuo and the resulting residue was neutralized with 1N NaOH at 0° C.until pH reached to 7. The reaction mixture was extracted with EtOAc(100 mL). The organic layer was collected and the aqueous layer wasfurther extracted with EtOAc (3×50 mL). All organics were combinedwashed with brine (2×25 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated to give yellow oil. Purification was accomplished by flashchromatography on silica gel using 5-25% EtOAc/hexanes gradient elutionto yield the title compound (3.4 g, 98%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.29 (d, J=7.9 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 4.31(t, J=6.5 Hz, 2H), 1.79-1.66 (m, 2H), 0.96 (t, J=7.5 Hz, 3H).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-isopropoxy-nicotinonitrile(D131)

To a mixture of 6-chloro-2-propoxy-nicotinonitrile (0.54 g, 3.0 mmol)and 3H-benzo[c][1,2]oxaborole-1,5-diol (0.40 g, 2.0 mmol) in DMF (10 mL)was added potassium carbonate (0.83 g, 6.0 mmol). The resultingsuspension was heated at 95° C. for 48 h. DMF was removed under reducedpressure, the residue was diluted with EtOAc (50 mL), washed with water(10 mL) and brine (2×10 mL), dried over Na₂SO₄, filtered, andconcentrated to give brown oil. Purification was accomplished by reversephase preparative HPLC using MeOH/H₂O (0.1% AcOH) as the eluent to yieldthe title compound (0.25 g, 26%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.25 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.79 (d, J=7.8 Hz,1H), 7.29 (s, 1H), 7.17-7.22 (m, 1H), 6.69 (d, J=8.6 Hz, 1H), 4.99 (s,2H), 4.07 (t, J=6.8 Hz, 2H), 1.65-1.55 (m, 2H), 0.81 (t, J=7.4 Hz, 3H);MS (ES) m/z: 311 (M+1)⁺; HPLC purity 98.36% (Maxplot), 97.66% (220 nm).

19ei6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-(2-hydroxy-ethylamino)-nicotinonitrile(D132)

2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethylamino]-6-chloro-nicotinamide(3)

To a solution of 2,6-dichloro-nicotinamide (1) (3 g, 15.7 mmol) inacetonitrile (anhydrous, 50 mL) were added22-(tert-butyl-dimethyl-silanyloxy)-ethylamine (2) (2.75 g, 15.7 mmol)and triethylamine (2.2 mL, 15.7 mmol). The reaction was heated at 60° C.for 2 days. The solution was cooled to room temperature and filtered.The filtrate was concentrated in vacuo. Purification was accomplished byBiotage silica gel chromatography with 10%-100% EtOAc/hexanes to afford2 g (40.6%) of the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.64 (br. s., 1H), 7.51 (d, J=8.2Hz, 1H), 6.47 (d, J=7.8 Hz, 1H), 5.66 (br. s., 2H), 3.79 (t, J=5.5 Hz,2H), 3.62 (q, J=5.5 Hz, 2H), 0.91 (s, 9H), 0.07 (s, 6H).

2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethylamino]-6-chloro-nicotinonitrile(4)

To a solution of2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-6-chloro-nicotinamide(3, 300 mg, 0.96 mmol) in acetonitrile (anhydrous, 50 mL) were addedpyridine (0.62 mL, 7.65 mmol) and POCl₃ (0.35 mL, 382 mmol). Thereaction was heated at 60° C. for 1 hour. After cooling to roomtemperature, NaOH solution (10% aq.) was slowly added till pH 9. EtOAc(200 mL) was added and the layers separated. The aqueous layer wasextracted with EtOAc (2×200 mL). The combined organic layer was driedover MgSO₄, filtered, and concentrated in vacuo. Purification wasaccomplished by silica gel chromatography, eluting with 1%-20%EtOAc/hexanes gradient, to afford 220 mg (78% yield) of the titledproduct.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.48 (d, J=7.9 Hz, 1H), 6.51 (d,J=7.9 Hz, 1H), 5.62 (br. s., 1H), 3.71 (t, J=5.2 Hz, 2H), 3.54 (q, J=5.3Hz, 2H), 0.83 (s, 9H), 0.00 (s, 6H).

6-(4-Bromo-3-formyl-phenoxy)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-nicotinonitrile(6)

To a solution of2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-6-chloro-nicotinonitrile(4, 1.1 g, 3.5 mmol) in DMF (80 mL) were added2-bromo-5-hydroxy-benzaldehyde (5, 0.75 g, 3.7 mmol) and K₂CO₃ (0.97 g,7.05 mmol). The reaction was heated at 80° C. for 24 h. The DMF wasremoved in vacuo. Purification was accomplished by Biotage silica gelchromatography with 1%-3% EtOAc/hexanes gradient to afford 1.26 g (75%yield) of the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.31 (s, 1H), 7.72 (d, J=2.8 Hz,1H), 7.62 (dd, J=8.6, 3.8 Hz, 2H), 7.21-7.26 (m, 1H), 6.17 (d, J=8.3 Hz,1H), 5.55 (t, J=4.9 Hz, 1H), 3.59 (t, J=5.3 Hz, 2H), 3.27 (q, J=5.2 Hz,2H), 0.85 (s, 9H), 0.00 (s, 6H)

2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethylamino]-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(7)

To a solution of6-(4-bromo-3-formyl-phenoxy)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-nicotinonitrile(6, 1.26 g, 2.65 mmol) in 1,4-dioxane (anhydrous, 150 mL) were addedbispinacolatodiboron (0.807 g, 3.18 mmol), PdCl₂(dppf) (0.19 g, 0.26mmol) and KOAc (0.78 g, 7.95 mmol). The solution was stirred at r.t.with N₂ bubbling for 30 minutes, then heated at 100° C. for 3 hours. Thesolution was filtered and concentrated in vacuo. Purification wasaccomplished by silica gel chromatography, eluting with 5%-25%EtOAc/hexanes gradient to afford 1.11 g (80% yield) of the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.63 (s, 1H), 7.94 (d, J=8.2 Hz,1H), 7.78 (d, J=1.9 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.37 (dd, J=8.1,2.1 Hz, 1H), 6.17 (d, J=8.2 Hz, 1H), 5.57 (br. s., 1H), 3.62 (t, J=5.1Hz, 2H), 3.32 (q, J=5.1 Hz, 2H), 1.40 (s, 12H), 0.88 (s, 9H), 0.03 (s,6H)

6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-(2-hydroxy-ethylamino)-nicotinonitrile(D132)

To a solution of2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(7, 1.11 g, 2.12 mmol) in MeOH (anhydrous, 60 mL) was added NaBH₄ (0.48g, 12.7 mmol). The reaction was stirred at r.t for 4 h, before theaddition of HCl (1 M, 20 mL). After overnight stirring, all volatilecomponents were removed. Purification was accomplished by preparativeHPLC, eluting with 5%-90% ACN/water gradient, to afford 86.3 mg (13%yield) of the title compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.20 (s, 1H), 7.87 (d, J=8.6 Hz, 1H),7.73 (d, J=8.2 Hz, 1H), 7.21 (s, 1H), 7.13-7.08 (m, 2H), 6.14 (d, J=8.2Hz, 1H), 4.96 (s, 2H), 4.59-4.55 (m, 1H), 3.32-3.29 (m, 2H), 3.16-3.10(m, 2H); ES MS: m/z 268 (M+H)⁺; HPLC: 98.95% (220 nm), 98.66% (MaxPlot).

19ej3-(cyclopentyloxy)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile(D133)

A solution of3-hydroxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile(0.500 g, 1.87 mmol), cyclopentyl iodide (0.65 mL, 5.61 mmol), andN,N-dimethylformamide (30 mL) under a nitrogen balloon was cooled to 0°C. on an ice water bath. Sodium hydride (0.224 g, 5.61 mmol) was addedand then the reaction was stirred for 5 minutes on the ice water bath.The reaction was then stirred at room temperature for 2 hours. Morecyclopentyl iodide (0.22 mL, 1.87 mmol) was added and the reaction wascooled to 0° C. on an ice water bath. Sodium hydride was added (0.075 g,1.87 mmol) and the reaction was stirred at 0° C. for 5 minutes. Thereaction was then stirred at room temperature for another 2 hours. Waterwas added to quench excess sodium hydride and the reaction was thenneutralized using 1 M HCl. Water was added and the solution wasextracted using ethyl acetate. The organic layer was washed with water,brine, dried over anhydrous sodium sulfate, and filtered. The solventwas removed under reduced pressure. The residue was purified by silicagel column using Combiflash to give3-(cyclopentyloxy)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile(0.396 g, 63% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (m, 2H), 1.38(m, 2H), 1.50 (m, 2H), 1.73 (m, 2H), 4.86 (m, 2H), 6.84 (s, 1H), 6.87(d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.58(s, 1H), 7.64 (d, J=8.0 Hz, 1H), 9.06 (s, 1H).

19ek3-(cyclopropylmethoxy)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile(D134)

A solution of bromomethyl cyclopropane (0.544 mL, 5.61 mmol), sodiumiodide (4.20 g, 28.05 mmol), and N,N-dimethylformamide (30 mL) under anitrogen balloon were stirred at 70° C. for 3 hours. The reaction wascooled to room temperature and3-hydroxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile(0.500 g, 1.87 mmol) and more N,N-dimethylformamide (30 mL) was added.The reaction was cooled to 0° C. in an ice water bath and sodium hydride(0.224 g, 5.61 mmol) was added. The reaction was stirred under nitrogenballoon at 0° C. for 5 minutes and then at room temperature overnight.Water was added to quench excess sodium hydride and the solution wasneutralized using 1 M HCl. Water was added and the solution wasextracted using ethyl acetate. The organic layer was washed with water,brine, dried over anhydrous sodium sulfate, and filtered. The solventwas removed under reduced pressure. The residue was purified by silicagel column using Combiflash to give3-(cyclopropylmethoxy)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile(0.225 g, 37% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.15 (d, J=4.5 Hz,2H), 0.43 (d, J=7.6 Hz, 2H), 1.06 (septet, J=6.7 Hz, 1H), 3.90, (d,J=6.9 Hz, 1H), 4.91 (s, 2H), 6.95 (m, 2H), 7.13 (d, J=8.2 Hz, 1H), 7.42(d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 9.12 (s, 1H).

19el3-(cyclopentylmethoxy)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile(D135)

This compound was prepared in the similar manner to that of D133.

ES(−) MS m/z=348 (M−H)⁻; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (m, 2H),1.37 (m, 4H), 1.47 (m, 2H), 2.07 (septet, J=7.2 Hz, 1H), 3.88 (d, J=6.4Hz, 2H), 4.88 (s, 2H), 6.88 (s, 1H), 6.90 (dd, J=8.1, 2.2 Hz, 1H), 7.21(d, J=8.4 Hz, 1H), 7.45 (dd, J=8.2, 2.0 Hz, 1H), 7.66 (m, 2H), 9.08 (s,1H).

19em6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-isobutoxy-nicotinonitrile(D136)

6-Chloro-2-isobutoxy-nicotinamide (3)

To a solution of 2,6-dichloro-nicotinamide (1) (3 g, 15.7 mmol) inacetonitrile (anhydrous, 30 mL) were added 2-methyl-propan-1-ol (2)(1.22 g, 16.5 mmol) and NaH (0.42 g, 16.5 mmol). The reaction was keptat r.t. O/N. The suspension was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by Biotage silica gelchromatography with 10%-80% EtOAc/hexanes gradient elution to afford2.39 g (66% yield) of the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46 (d, J=7.8 Hz, 1H), 7.70 (br.s., 1H), 7.06 (d, J=7.8 Hz, 1H), 6.09 (br. s., 1H), 4.30 (d, J=6.6 Hz,2H), 2.25-2.11 (m, 1H), 1.07 (d, J=6.6 Hz, 6H).

6-Chloro-2-isobutylamino-nicotinonitrile (4)

To a solution of 6-chloro-2-isobutoxy-nicotinamide (3, 2.39 g, 10.4mmol) in acetonitrile (anhydrous, 150 mL) were added pyridine (6.75 mL,83.5 mmol) and POCl₃ (3.82 mL, 41.7 mmol). The reaction was heated at55° C. for 3 hours. After cooling to room temperature, NaOH solution(10% aq.) was slowly added till pH 9. EtOAc (60 mL) was added and thelayers separated. The aqueous layer was extracted with EtOAc (2×60 mL).The combined organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. Purification was accomplished by silica gelchromatography, eluting with 2%-30% EtOAc/hexanes gradient, to afford 2g (91% yield) of the title product.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80 (d, J=8.0 Hz, 1H), 6.99 (d,J=8.0 Hz, 1H), 4.20 (d, J=6.6 Hz, 2H), 2.21-2.09 (m, 1H), 1.05 (d, J=6.6Hz, 6H).

6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-isobutoxy-nicotinonitrile(D136)

To a solution of 6-chloro-2-isobutylamino-nicotinonitrile (4, 1.12 g,5.33 mmol) in DMF (anhydrous, 30 mL) were added3H-benzo[c][1,2]oxaborole-1,5-diol (400 mg, 2.67 mmol) and Cs₂CO₃ (1.91g, 5.87 mmol). The reaction was heated at 80° C. for 2 h by microwave.Then DMF was evaporated in vacuo. Purification was accomplished bypreparative HPLC, eluting with 5%-90% ACN/water gradient, to afford 250mg (29% yield) of the title compound as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.23 (br s, 1H), 8.20 (d, J=8.2 Hz, 1H),7.77 (d, J=7.9 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H),4.97 (s, 2H), 3.89 (d, J=6.6 Hz, 2H), 1.95-1.80 (m, 1H), 0.80 (d, J=6.6Hz, 6H); ES MS: m/z 323 (M−H)⁻; HPLC: 99.25% (220 nm), 99.43% (MaxPlot).

19en5-[2-Cyano-4-(formylaminomethyl)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole(D137)

This compound was prepared from 2-fluoro-5-formylbenzonitrile and4-bromo-3-hydroxymethylphenol in the similar manner to that of D25.

¹H NMR (300 MHz, DMSO-d₆) ppm 4.30 (d, J=6.2 Hz, 2H), 4.94 (s, 2H),7.0-7.1 (m, 3H), 7.56 (dd, J=8.8, 1.2 Hz, 1H), 7.7-7.8 (m, 2H), 8.13 (s,1H), 8.56 (br s, 1H), 9.21 (s, 1H).

19eo5-(2-Aminomethyl-4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborolehydrochloride (D138)

This compound was prepared from D137 in the similar manner to that ofD26.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 4.04 (br s, 2H), 4.96 (s, 2H), 7.06-7.16(m, 3H), 8.05 (d, J=2.3 Hz, 1H), 8.45 (br s, 3H), 9.27 (s, 1H).

19ep Methyl4-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yloxy)-3-fluorobenzoate(D139)

Step 1

A mixture of 4-bromo-3-(1,3-dioxolan-2-yl)phenol (7.1 g, 29 mmol, 1 eq),3,4-difluoro-methylbenzorate (5 g, 29 mmol, 1 eq), potassium carbonate(6 g, 43.5 mmol, 1.5 eq) in DMF (29 mL). Reaction was stirred at 100° C.over night. TLC showed that reaction was completed. After cooling toroom temperature, the residue was removed by filtration. The residue waswashed with EtOAc. The organics were combined and concentrated via Rotavapor. The residue was poured into ETOAC and water. The Organic layerswas separated and washed with brine and dried over sodium sulfateanhydrous. Filter and concentrated to get the titled compound as crude,light brown oil, which was used for next step without purification.

Step 2

To a solution of methyl4-(4-bromo-3-(1,3-dioxolan-2-yl)phenoxy)-3-fluorobenzoate in 30 mL ofTHF was added 20 ml of 3M HCl (made from 6M HCl and water 1:1), refluxedfor 2 hour. TLC showed no SM (Hexane:EtOAc 7:3). The reaction was cooledto RT. Add 1N NaOH (60 ml), Rota vapor to remove half of the solvent,extracted with EtOAc. The organics were washed with water, brine, driedover Na2SO4, filtered, and concentrated to get light brown oil. Standbyover weekend to get solidified solid. Filtered, washed with Hexane/EtOActo collect the off-white powder 10.2 g 99.6 Yield % (two steps)

Step 3

To a solution of methyl 4-(4-bromo-3-formylphenoxy)-3-fluorobenzoate;(10 g, 28.3 mmol), KOAc (8.33 g, 84.9 mmol), bis(pinacolato)diboron(8.63 g, 34 mmol) in anhydrous 1,4-dioxane (120 mL) was addedPdCl2(dppf)₂ (578 mg; 2.5 mol % CAS #72287-26-4, Aldrich catalog#379670). The reaction mixture was degassed with N₂, and then heated at80° C. with magnetic stirring. The reaction was monitored with TLC andwas completed overnight. The mixture was cooled to room temperature,filtered through celite and washed with ethyl acetate and thenevaporated. The residue was dissolved in minimum EtOAc and passedthrough a very short but big silica gel column eluted with a mixedsolvent of hexane:EtOAc (3:1, v/v) to remove dark color giving lightyellow oil. Chromatography on silica gel again (Hexane/EtOAc 7:3). Thefirst portion is white solid, NMR indicated as bis(pinacolato)diboron(no aromatic signals). The product was collected and concentrated toafford methyl3-fluoro-4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzoateas colorless oil 9.5 g. Yield 84% ¹H NMR (DMSO-d6, 300 MHz): δ=10.38 (s,1H), 7.91 (dd, J=2.1, 13.2 Hz, 1H), 7.82 (d, J=7.8 Hz, 2H), 7.42 (d,J=2.7 Hz, 2H), 7.32 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), and 1.32 (s, 12H)ppm.

Step 4

To a solution of methyl3-fluoro-4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzoate(5 g, 12.5 mmol) in MeOH (125 mL) was added NaBH₄ (709 mg; 18.75 mmol)in portions under N2 at 0° C. in an ice-bath. The reaction was stirredat 0° C. to room temperature. The reaction was monitored with TLC andwas completed overnight. The mixture was cooled to rt. Solvent wasevaporated to half volume via Rota vapor. The mixture was then cooled to0° C., and quenched by adding water (12 mL) following by adding 6 N HCl(12 mL). Stirred at rt for 30 min, white Solid precipitated out.Filtered. The solid was gummy. The solid was suspended in water,sonicated for 1 hr. Filtered, washed with more water. Filtered, dried toget white solid. D139 (2.1 g). Yield 55.7%. M.p. 149-152° C. MS (ESI):m/z=303 (M+1, positive) and 301 (M−1, negative). HPLC (220 nm): 97.27%purity. (254 nM): 97.29% purity ¹H NMR (DMSO-d6, 300 MHz): δ=9.19 (s,1H), 7.88 (dd, J=1.8, 11.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.75 (d,J=8.1 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 4.93 (s,2H), and 3.84 (s, 3H).

19eq D140

This compound is made in a similar manner to D130 using2-isopropoxyethanol instead of propanol.

19er D141

This compound is made in a similar manner to D130 using 3-acetylpropanolinstead of propanol.

19es D142

This compound is made from D10 and 2-isopropoxyethanol by Mitsunobureaction.

19et D143

This compound is made from D10 and 3-acetylpropanol by Mitsunobureaction.

19eu D144

This compound is made from D14 and 2-isopropoxyethanol by Mitsunobureaction.

19ev D145

This compound is made from D14 and 3-acetylpropanol by Mitsunobureaction.

19ew D146

This compound is made from D10 and 2-hydroxyethyl acetate by Mitsunobureaction.

19ex D147

This compound is made from D14 and 2-hydroxyethyl acetate by Mitsunobureaction.

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-4-methyl-benzenesulfonamide(D148)

To a 20 mL scintillation vial containing5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (144 mg, 0.56mmol, 1.1 eq.), 4-methyl-benzenesulfonyl chloride (118.4 mg, 0.62 mmol,1.1 eq.) in DCM (10.0 mL) was added Et₃N (160 μL, 1.12 mmol, 2.0 eq.)drop wise. The mixture was stirred at room temperature overnight. Themixture was carefully treated with aqu. NH₄Cl (10 mL) and the layerswere separated. The aqueous was extracted with DCM (2×5 mL), combinedorganic phase was washed with H₂O (10 mL), brine (10 mL), dried overMgSO₄, filtered and the filtrate was concentrated under reducedpressure. The residue was applied to silica chromatography eluting withEtOAc/Heptanes (0:100 to 80:20) to giveN-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-4-methyl-benzenesulfonamideas a white solid. LCMS (m/z) 432 (M+23); ¹H NMR (400 MHz, DMSO-d) δ ppm¹H NMR (DMSO-d₆) δ: 9.11 (s, 1H), 8.08 (t, J=6.3 Hz, 1H), 7.65-7.74 (m,3H), 7.38 (d, J=8.0 Hz, 2H), 7.23-7.31 (m, J=8.6 Hz, 2H), 6.95-7.00 (m,2H), 6.89-6.95 (m, 2H), 4.92 (s, 2H), 3.95 (d, J=6.3 Hz, 2H), 2.38 (s,3H).

3-Chloro-N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-benzenesulfonamide(D149)

D149 was prepared using a procedure similar to that of D148. LCMS (m/z)452 (M+23); ¹H NMR (DMSO-d₆) δ: 9.11 (s, 1H), 8.36 (t, J=6.3 Hz, 1H),7.66-7.77 (m, 4H), 7.59 (t, J=8.1 Hz, 1H), 7.25 (d, J=8.6 Hz, 2H),6.87-6.98 (m, 4H), 4.93 (s, 2H), 4.05 (d, J=6.3 Hz, 2H).

2-Chloro-N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-benzenesulfonamide(D150)

D150 was prepared using a procedure similar to that of D148. LCMS (m/z)452 (M+23); ¹H NMR (DMSO-d₆) δ: 9.11 (s, 1H), 8.45 (t, J=6.2 Hz, 1H),7.88-7.93 (m, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.57-7.61 (m, 2H), 7.44-7.51(m, 1H), 7.23 (d, J=8.6 Hz, 2H), 6.84-6.92 (m, 4H), 4.94 (s, 2H), 4.11(d, J=6.2 Hz, 2H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-methanesulfonamide(D151)

D151 was prepared using a procedure similar to that of D148. LCMS (m/z)356 (M+23); ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 7.69 (d, J=7.9 Hz, 1H),7.52 (t, J=6.3 Hz, 1H), 7.33-7.39 (m, J=8.6 Hz, 2H), 7.00-7.07 (m, 2H),6.90-6.97 (m, 2H), 4.90 (s, 2H), 4.13 (d, J=6.3 Hz, 2H), 2.85 (s, 3H).

5-(5-Aminomethyl-pyridin-2-yloxy)-3H-benzo[c][1,2]oxaborol-1-ol (D152)

To a 50 mL round-bottom flask fitted with magnetic stirring bar wasadded6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(1.0 g, 4.0 mmol, 1.0 eq.), followed by addition of EtOH (40 mL) and THF(15 mL). The flask was evacuated and recharged with N₂ twice. To thestirring solution was added 5% Pd/C (300 mg) and the flask was evacuatedand recharged with H₂ three times. The resulting suspension was stirredunder a H₂ balloon at room temperature over 3 days. The mixture wasfiltered through a short pack of celite and washed with EtOH (3×25 mL).The combined filtrate was concentrated under reduced pressure, theresidue was applied to silica chromatography eluting with MeOH/DCM(0:100 to 10:90) to give a white solid. The solid was dissolved inminimum amount of MeOH and carefully treated with HCl in Et₂O. Theprecipitate was collected by filtration and washed with Et₂O to give5-(5-aminomethyl-pyridin-2-yloxy)-3H-benzo[c][1,2]oxaborol-1-olhydrochloride a white solid. ¹H NMR (DMSO-d₆) δ: 9.95 (br. s., 1H), 8.28(d, J=2.2 Hz, 1H), 8.11 (dd, J=8.5, 2.4 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H),7.07-7.14 (m, 2H), 7.05 (dd, J=7.9, 2.0 Hz, 1H), 4.94 (s, 2H), 4.14 (t,J=5.6 Hz, 2H).

5-{4-[(Cyclohexylmethyl-amino)-methyl]-phenoxy}-3H-benzo[c][1,2]oxaborol-1-ol(D153)

To a solution of 5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol(150 mg, 0.59 mmol, 1.0 eq.) in EtOH (5.0 mL) was addedcyclohexanecarbaldehyde (280 μL, 2.36 mmol, 4.0 eq.). The mixture wasstirred at room temperature for 30 minutes. After cooling to 0° C.,NaBH₄ (89 mg, 0.36 mmol, 4.0 eq.) was added in portions and the mixturewas allowed to warm to room temperature and stirred for 2 h. The mixturewas carefully treated with dilute HCl (5 mL) and aqueous phase wasextracted with EtOAc (3×10 mL). Combined organic extracts was washedwith brine (10 mL), dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure. The residue was applied to silicachromatography eluting with MeOH/DCM (0:100 to 10:90) to give5-{4-[(cyclohexylmethyl-amino)-methyl]-phenoxy}-3H-benzo[c][1,2]oxaborol-1-olas a white solid. LCMS (m/z) 352 (M+H); ¹H NMR (DMSO-d₆) δ: 9.08 (s,1H), 7.68 (d, J=8.0 Hz, 1H), 7.30-7.37 (m, J=8.5 Hz, 2H), 6.95-7.02 (m,2H), 6.88-6.95 (m, 2H), 4.89 (s, 2H), 3.64 (s, 2H), 2.31 (d, J=6.6 Hz,2H), 1.67-1.77 (m, 2H), 1.56-1.66 (m, 3H), 1.30-1.44 (m, 1H), 1.02-1.23(m, 3H), 0.77-0.91 (m, 2H).

5-(4-Cyclohexylaminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (D154)

D154 was prepared using a procedure similar to that of D153. LCMS (m/z)338 (M+H); ¹H NMR (DMSO-d₆) δ: 9.08 (br. s., 1H), 7.68 (d, J=8.0 Hz,1H), 7.31-7.38 (m, J=8.5 Hz, 2H), 6.95-7.00 (m, 2H), 6.89-6.95 (m, 2H),4.89 (s, 2H), 3.68 (s, 2H), 2.35 (tt, J=9.9, 3.7 Hz, 1H), 1.78-1.88 (m,2H), 1.59-1.70 (m, 2H), 1.47-1.56 (m, 1H), 0.97-1.22 (m, 5H).

5-(4-{[(1H-Pyrrol-2-ylmethyl)-amino]-methyl}-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol(D155)

D155 was prepared using a procedure similar to that of D153. LCMS (m/z)335 (M+H); ¹H NMR (DMSO-d₆) δ: 9.08 (br. s., 1H), 7.68 (d, J=7.9 Hz,1H), 7.32-7.38 (m, J=8.5 Hz, 2H), 6.96-7.02 (m, 2H), 6.89-6.96 (m, 2H),6.61 (td, J=2.6, 1.6 Hz, 1H), 5.89 (q, J=2.6 Hz, 1H), 5.83-5.87 (m, 1H),4.90 (s, 2H), 4.07 (br. s., 1H), 3.63 (s, 2H), 3.60 (s, 2H), 3.31 (br.s., 1H).

5-{4-[(2-Bromo-benzylamino)-methyl]-phenoxy}-3H-benzo[c][1,2]oxaborol-1-ol(D156)

D156 was prepared using a procedure similar to that of D153. LCMS (m/z)424 (M⁺); ¹H NMR (CHLOROFORM-d) δ: 7.71 (br. s., 1H), 7.55 (d, J=7.9 Hz,1H), 7.41 (dd, J=7.6, 1.5 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.26-7.32 (m,1H), 7.10-7.19 (m, 2H), 7.01 (d, J=8.5 Hz, 3H), 6.96 (br. s., 1H), 6.89(s, 1H), 5.29 (br. s., 1H), 5.04 (br. s., 2H), 3.92 (s, 2H), 3.81 (s,2H).

5-{4-[(3-Bromo-benzylamino)-methyl]-phenoxy}-3H-benzo[c][1,2]oxaborol-1-ol(D157)

D157 was prepared using a procedure similar to that of D153. LCMS (m/z)424 (M⁺); ¹H NMR (CHLOROFORM-d) δ: 7.68 (br. s., 1H), 7.52 (s, 1H), 7.38(dt, J=7.9, 1.4 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.26-7.29 (m, 1H), 7.19(t, J=7.7 Hz, 1H), 6.96-7.03 (m, 1H), 7.01 (d, J=8.5 Hz, 2H), 6.89 (s,1H), 5.02 (br. s., 2H), 3.80 (d, J=5.5 Hz, 4H), 2.17 (s, 1H).

5-{4-[(2-Methoxy-benzylamino)-methyl]-phenoxy}-3H-benzo[c][1,2]oxaborol-1-ol(D158)

D158 was prepared using a procedure similar to that of D153. LCMS (m/z)376 (M+H); ¹H NMR (CHLOROFORM-d) δ: 7.64 (s, 1H), 7.34 (d, J=8.4 Hz,2H), 7.27 (s, 1H), 7.24 (br. s., 1H), 6.85-7.02 (m, 6H), 5.00 (s, 2H),3.85 (s, 2H), 3.83 (s, 3H), 3.78 (s, 2H), 2.16 (s, 1H).

5-[4-(Benzylamino-methyl)-phenoxy]-3H-benzo[c][1,2]oxaborol-1-ol (D159)

D159 was prepared using a procedure similar to that of D153. LCMS (m/z)346 (M+H); ¹HNMR (CHLOROFORM-d) δ: 7.66 (br. s., 1H), 7.31-7.38 (m, 6H),7.28 (d, J=2.5 Hz, 0H), 6.99 (s, 3H), 6.88 (br. s., 1H), 5.01 (s, 2H),3.88 (s, 1H), 3.84 (s, 2H), 3.81 (s, 2H).

5-{4-[(2-Methyl-benzylamino)-methyl]-phenoxy}-3H-benzo[c][1,2]oxaborol-1-ol(D160)

D160 was prepared using a procedure similar to that of D153. LCMS (m/z)360 (M+H); ¹H NMR (CHLOROFORM-d) δ: 7.64-7.72 (m, 1H), 7.32-7.39 (m,3H), 7.18 (dd, J=5.3, 3.4 Hz, 2H), 7.14-7.21 (m, 1H), 6.98 (d, J=8.5 Hz,3H), 6.87 (s, 1H), 4.99 (s, 2H), 3.94 (d, J=1.4 Hz, 4H), 2.30 (s, 3H).

5-[4-(Isopropylamino-methyl)-phenoxy]-3H-benzo[c][1,2]oxaborol-1-ol(D161)

D161 was prepared using a procedure similar to that of D153. LCMS (m/z)298 (M+H); ¹H NMR (CHLOROFORM-d) δ: 7.61 (d, J=8.4 Hz, 3H), 6.99 (d,J=8.1 Hz, 2H), 6.85 (br. s., 2H), 5.00 (s, 2H), 3.98 (s, 2H), 2.15 (s,1H), 1.42 (d, J=6.5 Hz, 6H).

3-{[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylamino]-methyl}-benzonitrile(D162)

D162 was prepared using a procedure similar to that of D153. LCMS (m/z)239 (M−131); ¹H NMR (DMSO-d₆) δ: 9.86 (br. s., 1H), 9.15 (br. s., 1H),8.06 (s, 1H), 7.83-7.93 (m, 2H), 7.65-7.75 (m, 1H), 7.58-7.65 (m, 3H),7.07 (d, J=8.6 Hz, 1H), 7.04-7.10 (m, 1H), 6.93-6.99 (m, 2H), 4.91 (s,2H), 4.14 (br. s., 4H).

4-{[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylamino]-methyl}-benzonitrile(D163)

D163 was prepared using a procedure similar to that of D153. LCMS (m/z)239 (M−131); ¹H NMR (DMSO-d₆) δ: 9.46-9.73 (m, 1H), 9.13 (s, 1H), 7.90(d, J=8.3 Hz, 2H), 7.72 (d, J=8.6 Hz, 3H), 7.52-7.56 (m, J=8.6 Hz, 2H),7.06-7.10 (m, J=8.6 Hz, 2H), 6.96 (s, 1H), 6.95 (d, J=0.5 Hz, 1H), 4.91(s, 2H), 4.22 (s, 2H), 4.09-4.17 (m, 2H).

5-{4-[(4-Nitro-benzylamino)-methyl]-phenoxy}-3H-benzo[c][1,2]oxaborol-1-ol(D164)

D164 was prepared using a procedure similar to that of D153. LCMS (m/z)239 (M−151); ¹H NMR (DMSO-d₆) δ: 9.11 (s, 1H), 8.22-8.27 (m, J=8.7 Hz,2H), 7.70 (d, J=8.9 Hz, 3H), 7.47 (s, 2H), 7.04-7.08 (m, J=8.5 Hz, 2H),6.93-6.97 (m, 2H), 4.90 (s, 2H), 4.09-4.23 (m, 2H), 3.94-4.05 (m, 2H).

N-(4-t[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylamino]-methyl-phenyl)-acetamide(D165)

D165 was prepared using a procedure similar to that of D153. LCMS (m/z)403 (M+H); ¹H NMR (DMSO-d₆) δ: 10.18 (s, 1H), 9.66 (br. s., 1H), 9.16(br. s., 1H), 7.74 (d, J=8.7 Hz, 1H), 7.59 (dd, J=16.0, 8.6 Hz, 4H),7.45 (d, J=8.6 Hz, 2H), 7.06 (d, J=8.6 Hz, 2H), 6.95 (s, 1H), 6.96 (d,J=3.8 Hz, 1H), 4.91 (s, 2H), 4.04 (br. s., 4H), 2.03 (s, 3H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-acetamide(D166)

To a 20 mL scintillation vial containing5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (150 mg, 0.59mmol, 1.0 eq.) in DCM (5.0 mL) was added Et₃N (180 μL, 1.3 mmol, 2.2eq.), followed by acetyl chloride (84 μL, 1.2 mmol, 2.0 eq.). Themixture was stirred at room temperature overnight. The mixture wasconcentrated under reduced pressure. The residue was applied to silicachromatography eluting with MeOH/DCM (0:100 to 10:90) to giveN-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-acetamideas a white solid. LCMS (m/z) 298 (M+H); ¹H NMR (CHLOROFORM-d) δ: 7.55(d, J=8.0 Hz, 1H), 7.11 (d, J=8.6 Hz, 2H), 6.74-6.83 (m, 3H), 6.68 (d,J=1.4 Hz, 1H), 4.79 (s, 2H), 4.21 (d, J=5.8 Hz, 2H), 1.84 (s, 3H).Amount obtained, 165 mg, 94.3% yield.

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-4-methyl-benzamide(D167)

D167 was prepared using a procedure similar to that of D166. LCMS (m/z)396 (M+23); ¹H NMR (CHLOROFORM-d) δ: 7.69 (d, J=8.2 Hz, 2H), 7.35 (d,J=6.8 Hz, 2H), 7.23 (d, J=7.9 Hz, 2H), 6.95-7.04 (m, 3H), 6.88 (br. s.,1H), 6.83-6.93 (m, 1H), 6.38 (br. s., 1H), 5.02 (s, 2H), 4.63 (d, J=5.7Hz, 2H), 2.39 (s, 3H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-3-methyl-benzamide(D168)

D168 was prepared using a procedure similar to that of D166. LCMS (m/z)374 (M+H); ¹H NMR (CHLOROFORM-d) δ: 7.68 (d, J=8.2 Hz, 1H), 7.63 (s,1H), 7.52-7.60 (m, 1H), 7.30-7.38 (m, 4H), 7.02 (dd, J=8.6, 2.7 Hz, 3H),6.89 (br. s., 1H), 6.39 (br. s., 1H), 5.02 (s, 2H), 4.64 (d, J=5.7 Hz,2H), 3.88 (s, 1H), 2.39 (s, 3H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-2-methyl-benzamide(D169)

D169 was prepared using a procedure similar to that of D166. LCMS (m/z)374 (M+H); ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.76 (s, 1H), 7.68 (d,J=8.0 Hz, 1H), 7.28-7.38 (m, 4H), 7.22 (d, J=7.4 Hz, 2H), 7.00-7.05 (m,2H), 6.91-6.96 (m, 2H), 4.89 (s, 2H), 4.41 (d, J=6.1 Hz, 2H), 2.31 (s,3H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-4-nitro-benzamide(D170)

D170 was prepared using a procedure similar to that of D166. LCMS (m/z)374 (M−30); ¹H NMR (DMSO-d₆) δ: 9.36 (s, 1H), 9.08 (s, 1H), 8.28-8.32(m, 2H), 8.08-8.12 (m, 2H), 7.68 (d, J=8.0 Hz, 1H), 7.34-7.38 (m, J=8.6Hz, 2H), 6.99-7.04 (m, 2H), 6.89-6.95 (m, 2H), 4.89 (s, 2H), 4.48 (d,J=5.9 Hz, 2H).

4-Cyano-N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-benzamide(D171)

D171 was prepared using a procedure similar to that of D166. LCMS (m/z)407 (M+23); ¹H NMR (DMSO-d₆) δ: 9.28 (s, 1H), 9.08 (s, 1H), 8.00-8.05(m, 2H), 7.93-7.97 (m, 2H), 7.68 (d, J=8.0 Hz, 1H), 7.32-7.37 (m, J=8.6Hz, 2H), 6.99-7.04 (m, 2H), 6.89-6.95 (m, 2H), 4.88 (s, 2H), 4.47 (d,J=5.9 Hz, 2H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-4-methoxy-benzamide(D172)

D172 was prepared using a procedure similar to that of D166. LCMS (m/z)390 (M+H); ¹H NMR (CHLOROFORM-d) δ: 7.74-7.78 (m, 1H), 7.76 (d, J=8.8Hz, 2H), 7.31 (dd, J=8.4, 1.9 Hz, 2H), 6.97 (s, 1H), 6.95 (d, J=0.7 Hz,1H), 6.92 (dd, J=8.1, 0.6 Hz, 1H), 6.85-6.89 (m, 2H), 6.81-6.84 (m, 1H),4.97 (s, 1H), 4.94 (s, 1H), 4.57 (d, J=5.2 Hz, 2H), 3.80 (d, J=1.0 Hz,3H).

4-Fluoro-N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-benzamide(D173)

D173 was prepared using a procedure similar to that of D166. LCMS (m/z)400 (M+23); ¹H NMR (CHLOROFORM-d) δ: 7.82 (dd, J=8.8, 5.3 Hz, 2H),7.55-7.72 (m, 1H), 7.30 (dd, J=8.7, 2.3 Hz, 2H), 7.01-7.09 (m, 3H), 6.96(d, J=8.5 Hz, 2H), 6.91 (dt, J=8.1, 2.3 Hz, 1H), 6.83 (d, J=2.0 Hz, 1H),4.95 (d, J=12.8 Hz, 2H), 4.56 (d, J=5.7 Hz, 2H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-4-trifluoromethyl-benzamide(D174)

D174 was prepared using a procedure similar to that of D166. LCMS (m/z)450 (M+23); ¹H NMR (CHLOROFORM-d) δ: 8.20 (s, 1H), 7.89-7.94 (m, J=8.2Hz, 2H), 7.79 (br. s., 1H), 7.64 (d, J=8.1 Hz, 1H), 7.56-7.62 (m, J=8.2Hz, 2H), 7.27 (d, J=8.6 Hz, 2H), 6.88-6.93 (m, 2H), 6.85 (dd, J=8.1, 2.0Hz, 1H), 6.78 (s, 1H), 4.88 (s, 2H), 4.52 (d, J=5.8 Hz, 2H).

Acetic acid1-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-1-methyl-ethylester (D175)

D175 was prepared using a procedure similar to that of D166. LCMS (m/z)406 (M+23); ¹H NMR (CHLOROFORM-d) δ: 7.68 (br. s., 1H), 7.23-7.28 (m,2H), 6.95-7.02 (m, 3H), 6.88 (s, 1H), 6.40 (br. s., 1H), 5.01 (s, 2H),4.46 (d, J=5.9 Hz, 2H), 2.06 (s, 3H), 2.03 (s, 1H), 1.66 (s, 6H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-isobutyramide(D176)

D176 was prepared using a procedure similar to that of D166. LCMS (m/z)326 (M+H); ¹H NMR (CHLOROFORM-d) δ: 7.68 (br. s., 1H), 7.24-7.28 (m,2H), 6.96-7.02 (m, 3H), 6.84-6.92 (m, 1H), 5.77 (br. s., 1H), 5.02 (s,2H), 4.43 (d, J=5.8 Hz, 2H), 1.19 (d, J=6.9 Hz, 6H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-2,2-dimethyl-propionamide(D177)

D177 was prepared using a procedure similar to that of D166. LCMS (m/z)340 (M+H); ¹H NMR (CHLOROFORM-d) δ: 7.66 (br. s., 1H), 7.21-7.26 (m,2H), 6.99 (d, J=8.5 Hz, 2H), 6.94-7.00 (m, 1H), 6.88 (s, 1H), 6.02 (br.s., 1H), 5.01 (s, 2H), 4.42 (d, J=5.7 Hz, 2H), 3.82 (br. s., 1H), 1.23(s, 9H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-propionamide(D178)

D178 was prepared using a procedure similar to that of D166. LCMS (m/z)312 (M+H); ¹H NMR (DMSO-d₆) δ: 9.08 (br. s., 1H), 8.24 (br. s., 1H),7.68 (d, J=8.0 Hz, 1H), 7.23-7.29 (m, J=8.5 Hz, 2H), 6.97-7.03 (m, 2H),6.93 (dd, J=8.0, 2.1 Hz, 1H), 6.90 (s, 1H), 4.89 (s, 2H), 4.23 (d, J=6.0Hz, 2H), 2.12 (q, J=7.6 Hz, 2H), 1.00 (t, J=7.6 Hz, 3H).

Cyclopentanecarboxylic acid4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylamide(D179)

D179 was prepared using a procedure similar to that of D166. LCMS (m/z)352 (M+H); ¹H NMR (CHLOROFORM-d) δ: 7.66 (d, J=8.1 Hz, 1H), 7.19 (d,J=8.5 Hz, 2H), 6.85-6.93 (m, 3H), 6.79 (s, 1H), 6.31 (br. s., 1H), 4.91(s, 2H), 4.34 (d, J=5.8 Hz, 2H), 1.64-1.83 (m, 6H), 1.45-1.54 (m, 2H).

Cyclohexanecarboxylic acid4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylamide(D180)

D180 was prepared using a procedure similar to that of D166. LCMS (m/z)366 (M+H); ¹H NMR (CHLOROFORM-d) δ: 7.71 (br. s., 1H), 7.24 (d, J=8.5Hz, 2H), 6.97 (d, J=8.4 Hz, 3H), 6.87 (s, 1H), 5.96 (br. s., 1H), 5.01(br. s., 2H), 4.42 (d, J=5.7 Hz, 2H), 1.88 (d, J=13.2 Hz, 2H), 1.77 (d,J=9.8 Hz, 2H), 1.66 (d, J=5.7 Hz, 1H), 1.46 (d, J=12.3 Hz, 2H),1.16-1.31 (m, 3H).

Furan-2-carboxylic acid4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylamide(D181)

D181 was prepared using a procedure similar to that of D166. LCMS (m/z)350 (M+H); ¹H NMR (CHLOROFORM-d) δ: 8.01 (s, 1H), 7.67 (d, J=8.0 Hz,1H), 7.38 (d, J=0.9 Hz, 1H), 7.24-7.31 (m, 2H), 7.08 (d, J=3.5 Hz, 1H),6.87-6.96 (m, 4H), 6.81 (s, 1H), 6.44 (dd, J=3.4, 1.7 Hz, 1H), 4.92 (s,2H), 4.53 (d, J=6.0 Hz, 2H).

Pyrrolidine-1-carboxylic acid4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylamide(D182)

D182 was prepared using a procedure similar to that of D166. LCMS (m/z)353 (M+H); ¹H NMR (CHLOROFORM-d) δ: 7.71 (d, J=8.1 Hz, 1H), 7.30 (d,J=8.4 Hz, 2H), 6.90-7.02 (m, 3H), 6.86 (d, J=1.1 Hz, 1H), 6.61 (br. s.,1H), 4.96-5.02 (m, 2H), 4.57 (br. s., 1H), 4.43 (d, J=5.7 Hz, 2H), 3.36(t, J=6.5 Hz, 4H), 1.90 (t, J=3.0 Hz, 3H), 1.90 (d, J=13.4 Hz, 1H).

[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-carbamicacid tert-butyl ester (D183)

D183 was prepared using a procedure similar to that of D166. LCMS (m/z)353 (M+H); ¹H NMR (CHLOROFORM-d) δ: 7.68 (d, J=8.1 Hz, 1H), 7.27 (d,J=8.5 Hz, 2H), 6.96-7.03 (m, 1H), 7.00 (d, J=8.5 Hz, 2H), 6.87 (s, 1H),5.00 (s, 2H), 4.30 (br. s., 2H), 1.46 (s, 9H).

1-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-3-phenyl-urea(D184)

To a 20 mL scintillation vial containing5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (150 mg, 0.59mmol, 1.0 eq.) in DCM (5.0 mL) was added phenylisocyanate (71 μL, 0.65mmol, 1.1 eq.). The mixture was stirred at room temperature overnight.The mixture was treated with H₂O (5 mL). The precipitate was collectedby filtration and washed with H₂O to give1-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-3-phenyl-ureaas a white solid. LCMS (m/z) 375 (M+H); ¹H NMR (DMSO-d₆) δ: 9.07 (s,1H), 8.51 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.37 (dd, J=8.6, 1.0 Hz, 2H),7.30-7.35 (m, J=8.6 Hz, 2H), 7.19 (t, J=8.0 Hz, 2H), 6.99-7.04 (m, 2H),6.88-6.95 (m, 3H), 6.58 (s, 1H), 4.89 (s, 2H), 4.27 (d, J=5.9 Hz, 2H).

1-Ethyl-3-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-urea(D185)

D185 was prepared using a procedure similar to that of D184. LCMS (m/z)327 (M+H); ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 7.67 (d, J=8.0 Hz, 1H),7.23-7.28 (m, J=8.6 Hz, 2H), 6.97-7.02 (m, 2H), 6.87-6.94 (m, 2H), 6.27(s, 1H), 5.85 (s, 1H), 4.88 (s, 2H), 4.16 (d, J=6.0 Hz, 2H), 3.00 (dd,J=7.1, 5.7 Hz, 2H), 0.97 (t, J=7.2 Hz, 3H).

1-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-3-p-tolyl-urea(D186)

D186 was prepared using a procedure similar to that of D184. LCMS (m/z)389 (M+H); ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.40 (s, 1H), 7.68 (d,J=8.0 Hz, 1H), 7.24-7.35 (m, 4H), 6.98-7.05 (m, 4H), 6.89-6.96 (m, 2H),6.53 (s, 1H), 4.89 (s, 2H), 4.26 (d, J=5.9 Hz, 2H), 2.19 (s, 3H).

1-Cyclohexyl-3-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-urea(D187)

D187 was prepared using a procedure similar to that of D184. LCMS (m/z)381 (M+H); ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 7.68 (d, J=8.0 Hz, 1H),7.26 (d, J=8.6 Hz, 2H), 7.00 (d, J=8.5 Hz, 1H), 6.97-7.03 (m, 1H),6.88-6.95 (m, 2H), 6.16 (s, 1H), 5.80 (d, J=8.0 Hz, 1H), 4.89 (s, 2H),4.17 (d, J=6.0 Hz, 2H), 1.71 (br. s., 2H), 1.60 (br. s., 2H), 1.44-1.55(m, 1H), 1.23 (br. s., 2H), 1.08 (br. s., 3H).

1-(4-Chloro-phenyl)-3-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-urea(D188)

D188 was prepared using a procedure similar to that of D184. LCMS (m/z)409 (M+H); ¹H NMR (DMSO-d₆) δ: 9.08 (br. s., 1H), 8.70 (s, 1H), 7.68 (d,J=8.0 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.42 (q, J=5.2 Hz, 1H), 7.30-7.38(m, 2H), 7.24 (d, J=8.9 Hz, 1H), 7.24 (q, J=5.1 Hz, 1H), 6.96-7.05 (m,1H), 7.02 (d, J=8.5 Hz, 1H), 6.88-6.96 (m, 2H), 6.66 (s, 1H), 4.89 (s,2H), 4.27 (d, J=5.9 Hz, 2H).

1-(4-Dimethylamino-phenyl)-3-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-urea(D189)

D189 was prepared using a procedure similar to that of D184. LCMS (m/z)418 (M+H); ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.13 (s, 1H), 7.67 (s, 1H),7.31 (s, 2H), 7.18 (d, J=9.1 Hz, 2H), 7.02 (d, J=8.6 Hz, 2H), 6.90 (s,2H), 6.63 (d, J=9.1 Hz, 2H), 6.41 (s, 1H), 4.89 (s, 2H), 4.26 (s, 2H),2.78 (s, 6H).

{1-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-thyl}-carbamicacid tert-butyl ester (D190)

To a 40 mL scintillation vial containing5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (350 mg, 1.37mmol, 1.0 eq.), EDCI (314.4 mg, 1.64 mmol, 1.2 eq.), HOBt (221.6 mg,1.64 mmol, 1.2 eq.) and Et₃N (0.46 mL mg, 3.29 mmol, 2.4 eq.) in DCM(15.0 mL) was added 2-tert-Butoxycarbonylamino-propionic acid (311.1 mg,1.64 mmol, 1.2 eq.) drop wise. The mixture was stirred at roomtemperature overnight. The mixture was treated with H₂O (10 mL) and thelayers were separated. The aqueous was extracted with DCM (2×10 mL),combined organic phase was washed with brine (10 mL), dried over MgSO₄,filtered and the filtrate was concentrated under reduced pressure. Theresidue was applied to silica chromatography eluting with MeOH/DCM(0:100 to 10:90) to give{1-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-thyl}-carbamicacid tert-butyl ester as a white solid. LCMS (m/z) 449 (M+23); ¹H NMR(DMSO-d₆) δ: 9.08 (s, 1H), 8.26 (t, J=5.7 Hz, 1H), 7.68 (d, J=8.0 Hz,1H), 7.22-7.31 (m, J=8.4 Hz, 2H), 6.96-7.01 (m, J=8.5 Hz, 2H), 6.88-6.95(m, 3H), 4.89 (s, 2H), 4.21-4.30 (m, 2H), 3.88-4.02 (m, 1H), 1.35 (s,9H), 1.18 (d, J=7.1 Hz, 3H).

{1-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-2-phenyl-ethyl}-carbamicacid tert-butyl ester) (D191)

D191 was prepared using a procedure similar to that of D190. LCMS (m/z)525 (M+23); ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.39 (t, J=5.7 Hz, 1H),7.68 (d, J=8.0 Hz, 1H), 7.18-7.27 (m, 8H), 6.89-6.99 (m, 4H), 4.89 (s,2H), 4.26 (d, J=5.9 Hz, 2H), 4.11-4.21 (m, 1H), 2.89-3.03 (m, 1H),2.71-2.86 (m, 1H), 1.29 (s, 9H).

{[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-methyl}-carbamicacid tert-butyl ester (D192)

D192 was prepared using a procedure similar to that of D190. LCMS (m/z)435 (M+23); ¹H NMR (CHLOROFORM-d) δ: 7.66 (br. s., 1H), 7.24 (d, J=6.2Hz, 1H), 7.26 (s, 1H), 6.93-6.98 (m, 3H), 6.85 (s, 1H), 6.73 (br. s.,1H), 4.98 (br. s., 2H), 4.44 (d, J=5.9 Hz, 2H), 3.83 (d, J=6.1 Hz, 2H),2.16 (s, 1H), 2.07 (s, 1H), 1.41 (s, 9H).

{1-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-3-methyl-butyl}-carbamicacid tert-butyl ester (D193)

D193 was prepared using a procedure similar to that of D190. LCMS (m/z)491 (M+23); ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.30 (t, J=5.9 Hz, 1H),7.68 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H),6.85-6.94 (m, 3H), 4.89 (s, 2H), 4.24 (d, J=5.9 Hz, 2H), 3.92-4.01 (m,1H), 1.39-1.48 (m, 1H), 1.35 (s, 9H), 1.26-1.32 (m, 1H), 0.84 (dd,J=10.5, 6.6 Hz, 7H).

{[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-methyl}-methyl-carbamicacid tert-butyl ester (D194)

D194 was prepared using a procedure similar to that of D190. LCMS (m/z)449 (M+23); ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.35 (t, J=5.5 Hz, 1H),7.68 (d, J=8.0 Hz, 1H), 7.29 (d, J=7.8 Hz, 2H), 6.97-7.04 (m, 2H),6.86-6.96 (m, 2H), 4.89 (s, 2H), 4.26 (d, J=6.0 Hz, 2H), 3.74-3.83 (m,2H), 2.80 (br. s., 3H), 1.38 (s, 4H), 1.29 (s, 5H).

2-Dimethylamino-N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-acetamide(D195)

D195 was prepared using a procedure similar to that of D190. LCMS (m/z)341 (M+H); ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.26 (t, J=6.2 Hz, 1H),7.68 (d, J=8.1 Hz, 1H), 7.25-7.31 (m, 2H), 6.97-7.02 (m, 2H), 6.88-6.95(m, 2H), 4.89 (s, 2H), 4.26 (d, J=6.2 Hz, 2H), 2.89 (s, 2H), 2.19 (s,6H).

1-Methyl-pyrrolidine-2-carboxylic acid4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylamide(D196)

D196 was prepared using a procedure similar to that of D190. LCMS (m/z)367 (M+H); ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.25 (t, J=6.2 Hz, 1H),7.68 (d, J=8.0 Hz, 1H), 7.22-7.29 (m, J=8.6 Hz, 2H), 6.96-7.03 (m, 2H),6.89-6.96 (m, 2H), 4.89 (s, 2H), 4.19-4.31 (m, 2H), 2.97-3.04 (m, 1H),2.74 (dd, J=9.4, 5.8 Hz, 1H), 2.26 (s, 3H), 2.19-2.24 (m, 1H), 2.01-2.12(m, 1H), 1.62-1.75 (m, 3H).

2-Dimethylamino-N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-3-phenyl-propionamide(D197)

D197 was prepared using a procedure similar to that of D190. LCMS (m/z)431 (M+H); ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.24 (t, J=5.9 Hz, 1H),7.68 (d, J=8.0 Hz, 1H), 7.12-7.24 (m, 5H), 7.03 (d, J=8.6 Hz, 2H),6.87-6.93 (m, 4H), 4.90 (s, 2H), 4.25-4.32 (m, 1H), 4.10 (dd, J=14.7,5.2 Hz, 1H), 3.27 (dd, J=9.5, 5.1 Hz, 1H), 2.96 (dd, J=13.1, 9.5 Hz,1H), 2.76 (dd, J=13.1, 5.1 Hz, 1H), 2.25 (s, 6H).

(2-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-pyrrolidine-1-carboxylicacid tert-butyl ester (D198)

D198 was prepared using a procedure similar to that of D190. LCMS (m/z)475 (M+23); ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.29-8.40 (m, 1H), 7.68(d, J=8.0 Hz, 1H), 7.25-7.34 (m, 2H), 6.95-7.03 (m, 2H), 6.87-6.95 (m,2H), 4.89 (s, 2H), 4.26-4.35 (m, 1H), 4.01-4.25 (m, 2H), 3.33-3.43 (m,1H), 3.22-3.30 (m, 2H), 1.66-1.87 (m, 3H), 1.38 (s, 3H), 1.25 (s, 6H).

2-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (D199)

D199 was prepared using a procedure similar to that of D190. LCMS (m/z)489 (M+23); ¹H NMR (DMSO-d₆) δ: 9.08 (s, 4H), 7.68 (d, J=7.5 Hz, 3H),7.67 (d, J=0.2 Hz, 1H), 7.27 (d, J=8.6 Hz, 7H), 6.97-7.02 (m, 7H), 4.89(s, 7H), 3.29 (s, 5H), 2.48 (dt, J=3.7, 1.8 Hz, 17H), 2.48 (d, J=7.6 Hz,17H).

2-Amino-N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-3-phenyl-propionamide(D200)

To a 20 mL scintillation vial{1-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylcarbamoyl]-2-phenyl-ethyl}-carbamicacid tert-butyl ester (190 mg, 0.38 mmol, 1.0 eq.) in DCM (5.0 mL) wasadded HCl (5.0 mL, 4.0M in 1,4-dioxane) and the mixture was stirred atroom temperature overnight. The mixture was concentrated under reducedpressure to give2-amino-N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-3-phenyl-propionamideas a light yellow glassy solid. LCMS (m/z) 403 (M+H); ¹H NMR (DMSO-d₆)δ: 8.91 (br. s., 1H), 8.32 (br. s., 3H), 7.70 (d, J=8.0 Hz, 1H),7.23-7.33 (m, 4H), 7.19-7.23 (m, 2H), 7.11 (d, J=8.6 Hz, 2H), 6.88-6.99(m, 4H), 4.90 (s, 2H), 4.27-4.35 (m, 1H), 4.15-4.24 (m, 1H), 3.98-4.06(m, 1H), 3.04 (d, J=7.2 Hz, 2H).

2-Amino-N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-propionamide(D201)

D201 was prepared using a procedure similar to that of D200. LCMS (m/z)327 (M+H); ¹H NMR (DMSO-d₆) δ: 8.88 (s, 1H), 8.14 (br. s., 3H), 7.69 (d,J=8.0 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 6.99-7.05 (m, 2H), 6.89-6.96 (m,2H), 4.89 (s, 2H), 4.32 (t, J=5.3 Hz, 2H), 3.82-3.91 (m, 1H), 1.36 (d,J=7.0 Hz, 3H).

2-Amino-4-methyl-pentanoic acid4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylamide(D202)

D202 was prepared using a procedure similar to that of D200. LCMS (m/z)369 (M+H); ¹H NMR (DMSO-d₆) δ: 9.07-9.15 (m, 2H), 8.29 (br. s., 3H),7.71 (d, J=8.0 Hz, 1H), 7.29-7.36 (m, J=8.6 Hz, 2H), 6.99-7.06 (m, 2H),6.88-6.96 (m, 2H), 4.90 (s, 2H), 4.26-4.36 (m, 2H), 3.72-3.83 (m, 1H),1.53-1.66 (m, 3H), 0.87 (dd, J=7.6, 6.2 Hz, 6H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-2-methylamino-acetamide(D203)

D203 was prepared using a procedure similar to that of D200. LCMS (m/z)327 (M+H); ¹H NMR (DMSO-d₆) δ: 7.70 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.4Hz, 2H), 7.03 (d, J=8.6 Hz, 2H), 6.89-6.96 (m, 2H), 4.90 (s, 2H), 4.33(d, J=5.9 Hz, 2H), 3.74 (t, J=5.7 Hz, 2H), 2.55 (dd, 3H).

Pyrrolidine-2-carboxylic acid4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylamide(D204)

D204 was prepared using a procedure similar to that of D200. LCMS (m/z)353 (M+H); ¹H NMR (DMSO-d₆) δ: 9.11 (br. s., 1H), 9.06 (t, J=5.8 Hz,1H), 7.70 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz,1H), 7.03 (q, J=4.9 Hz, 1H), 6.89-6.97 (m, 2H), 4.90 (s, 2H), 4.33 (d,J=5.8 Hz, 2H), 4.18 (br. s., 1H), 3.17-3.26 (m, 2H), 2.23-2.35 (m, 1H),1.79-1.94 (m, 3H).

Piperidine-2-carboxylic acid4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzylamide(D205)

D205 was prepared using a procedure similar to that of D200. LCMS (m/z)367 (M+H); ¹H NMR (DMSO-d₆) δ: 9.12 (br. s., 1H), 9.03 (t, J=5.8 Hz,1H), 8.62-8.72 (m, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H),6.99-7.05 (m, 2H), 6.89-6.96 (m, 2H), 4.90 (s, 2H), 4.32 (dd, J=5.6, 3.2Hz, 2H), 3.73-3.82 (m, 1H), 3.25-3.40 (m, 2H), 3.20 (d, J=12.5 Hz, 1H),2.86-2.95 (m, 0H), 2.12 (d, J=12.0 Hz, 1H), 1.44-1.79 (m, 3H).

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acidhydrazide (D206)

D206 was prepared using a procedure similar to that of D200. LCMS (m/z)285 (M+H); ¹H NMR (DMSO-d₆) δ: 11.68 (s, 1H), 7.92-8.04 (m, 2H), 7.79(d, J=8.0 Hz, 1H), 7.08-7.15 (m, 3H), 7.06 (dd, J=8.0, 2.1 Hz, 1H), 4.94(s, 2H).

2-Amino-N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-acetamide(D207)

D207 was prepared using a procedure similar to that of D200. LCMS (m/z)313 (M+23); ¹H NMR (DMSO-d₆) δ: 8.95 (br. s., 1H), 8.16 (br. s., 2H),7.71 (d, J=8.0 Hz, 1H), 7.29-7.36 (m, 2H), 6.98-7.06 (m, 2H), 6.88-6.97(m, 2H), 4.90 (s, 2H), 4.32 (d, J=5.9 Hz, 2H), 3.47-3.67 (m, 2H).

6-(1-Hydroxy-3-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile(D208)

To a suspension of6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile(105 mg, 0.3 mmol, 1.0 eq.) in THF (5.0 mL) at 0° C. was added MeMgBr(0.15 mL, 0.45 mmol, 1.5 eq.) drop wise. The mixture was stirred at 0°C. for 20 minutes and allowed to warm to room temperature in another 1h. After cooling to 0° C., the clear solution was carefully treated withH₂O (1 mL), followed by slow addition of HCl (10 mL, 3N). The resultingyellow suspension was allowed to ward to room temperature gradually andstirred for 2 h. The mixture was then treated with sat. NaHCO₃ drop wiseuntil PH reaching 7 and was extracted with EtOAc (3×10 mL). Combinedorganic extracts was washed with brine (10 mL), dried over MgSO₄,filtered and the filtrate was concentrated under reduced pressure. Theresidue was applied to silica chromatography eluting with MeOH/DCM(0:100 to 10:90) to give6-(1-hydroxy-3-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrileas a white solid. LCMS (m/z) 267 (M+H); ¹H NMR (DMSO-d₆) δ: 9.19 (s,1H), 8.71 (dd, J=2.3, 0.6 Hz, 1H), 8.38 (dd, J=8.7, 2.4 Hz, 1H), 7.80(d, J=7.9 Hz, 1H), 7.28-7.35 (m, 2H), 7.20 (dd, J=7.9, 2.0 Hz, 1H), 5.26(q, J=6.5 Hz, 1H), 1.45 (d, J=6.6 Hz, 3H).

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzaldehyde(D209)

To a solution of 4-fluoro-benzaldehyde (5.4 mL, 50.0 mmol, 1.0 eq.),4-bromo-3-hydroxymethyl-phenol (10.6 g, 50.0 mmol, 1.0 eq.) in DMF(140.0 mL) was added K₂CO₃ (8.3 g, 60.0 mmol, 1.2 eq.) under nitrogenatmosphere. The mixture was heated at 80° C. overnight. After cooling toroom temperature, the mixture was poured into EtOAc (10 mL) and sat. H₂O(100 mL). The layers were separated and the aqueous phase was extractedwith EtOAc (3×100 mL). Combined organic extracts was washed with brine(100 mL), dried over MgSO₄, filtered and the filtrate was concentratedunder reduced pressure. The residue was applied to silica chromatographyeluting with MeOH/DCM (0:100 to 10:90) to give4-(4-bromo-3-hydroxymethyl-phenoxy)-benzaldehyde as a yellow oil. ¹H NMR(CHLOROFORM-d) δ: 9.93 (s, 1H), 7.80-7.89 (m, 2H), 7.55 (d, J=8.6 Hz,1H), 7.27 (d, J=3.1 Hz, 1H), 7.06 (d, J=8.7 Hz, 2H), 6.89 (dd, J=8.6,2.9 Hz, 1H), 4.74 (s, 2H). Amount obtained, 15.2 g, 99% yield.

To a suspension of 44-(4-bromo-3-hydroxymethyl-phenoxy)-benzaldehyde as(15.2 g, 49.5 mmol, 1.0 eq) in DCM (250 mL) was added3,4-dihydro-2H-pyran (6.7 mL, 74.2 mmol, 1.5 eq.), followed bycamphorsulfonic acid (300 mg). The mixture was stirred at roomtemperature for 2 h. After adding K₂CO₃ (1 g), the mixture was washedwith H₂O (150 mL), brine (150 mL). The organic phase was dried overMgSO₄, filtered and the filtrate was concentrated under reducedpressure. The oily residue was applied to silica chromatography elutingwith EtOAc/Heptanes (0:100 to 50:50) to give4-[4-bromo-3-(tetrahydro-pyran-2-yloxymethyl)-phenoxy]-benzaldehyde as alight yellow oil. ¹H NMR (CHLOROFORM-d) δ: 9.93 (s, 1H), 7.81-7.89 (m,2H), 7.54 (d, J=8.6 Hz, 1H), 7.29 (d, J=2.9 Hz, 1H), 7.04-7.11 (m, 2H),6.87 (dd, J=8.6, 2.9 Hz, 1H), 4.81 (d, J=14.0 Hz, 1H), 4.76 (t, J=3.4Hz, 1H), 4.55 (d, J=14.0 Hz, 1H), 3.88 (ddd, J=11.3, 8.6, 3.1 Hz, 1H),3.51-3.61 (m, 1H), 1.71-1.88 (m, 6H).

To a solution of4-[4-bromo-3-(tetrahydro-pyran-2-yloxymethyl)-phenoxy]-benzaldehyde(1.17 g, 3.0 mmol, 1.0 eq.) in 1,4-dioxane (20 mL) was addedbis-pinacol-diboron (838 mg, 3.3 mmol, 1.1 eq.), KOAc (883 mg, 9.0 mmol,3.0 eq.) and PdCl₂(dppf)₂ (65.8 mg, 0.09 mmol, 0.03 eq.). The mixturewas degassed with N₂ and heated at 80° C. overnight. After cooling toroom temperature, the mixture was filtered though a short pack of celiteand the filtrate was concentrated under reduced pressure. The residuewas applied to silica chromatography eluting with EtOAc/Heptanes (0:100to 70:30) to give4-[3-(tetrahydro-pyran-2-yloxymethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-benzaldehydeas a clear oil. ¹H NMR (CHLOROFORM-d) δ: 9.93 (s, 1H), 7.84 (d, J=8.8Hz, 2H), 7.26 (s, 1H), 7.05-7.11 (m, 2H), 6.95 (dd, J=8.2, 2.4 Hz, 1H),4.95 (d, J=13.2 Hz, 1H), 4.84 (d, J=13.3 Hz, 1H), 4.75 (t, J=3.5 Hz,1H), 3.89 (ddd, J=11.3, 8.4, 3.0 Hz, 1H), 3.48-3.59 (m, 1H), 1.55-1.75(m, 6H), 1.34 (s, 12H).

To a suspension of4-[3-(tetrahydro-pyran-2-yloxymethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-benzaldehyde(1.4 g, 3.2 mmol, 1.0 eq.) in EtOH (15 mL) at 0° C. was added HCl (15mL, 3N). The mixture was stirred at 0° C. for 20 minutes and allowed towarm to room temperature in another 1 h. The mixture was then treatedwith sat. NaHCO₃ drop wise until PH reaching 7. The precipitate wascollected by filtration, washed with H₂O to give4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzaldehyde asa white solid. LCMS (m/z) 255 (M+H); ¹H NMR (DMSO-d₆) δ: 9.92 (s, 1H),9.19 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.92 (q, J=4.6 Hz, 1H), 7.78 (d,J=8.0 Hz, 1H), 7.16 (d, J=8.7 Hz, 2H), 7.12-7.19 (m, 1H), 7.09 (dd,J=8.0, 2.1 Hz, 1H), 4.95 (s, 2H).

5-(4-Methylaminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (D210)

To a solution of4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-enzaldehyde(76.2 mg, 0.3 mmol, 1.0 eq.) in MeOH (3.0 mL) was added dimethylamine(170 μL, 0.33 mmol, 1.1 eq.). The mixture was stirred at roomtemperature for 30 minutes. After cooling to 0° C., NaBH₄ (11.3 mg, 0.3mmol, 1.0 eq.) was added in portions and the mixture was allowed to warmto room temperature and stirred for 2 h. The mixture was carefullytreated with dilute HCl (5 mL) and aqueous phase was extracted withEtOAc (3×10 mL). Combined organic extracts was washed with brine (10mL), dried over MgSO₄, filtered and the filtrate was concentrated underreduced pressure. The residue was applied to silica chromatographyeluting with MeOH/DCM (0:100 to 10:90) to give5-(4-methylaminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol as a whitesolid. LCMS (m/z) 270 (M+H); ¹H NMR (DMSO-d₆) δ: 7.67-7.74 (m, 1H),7.41-7.46 (m, J=8.5 Hz, 2H), 7.00-7.07 (m, 2H), 6.91-6.98 (m, 2H), 4.91(s, 2H), 4.53 (s, 3H), 3.85 (s, 2H).

5-(4-Dimethylaminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (D211)

D211 was prepared using a procedure similar to that of D210. LCMS (m/z)284 (M+H); ¹H NMR (DMSO-d₆) δ: 9.09 (br. s., 1H), 7.67-7.73 (m, 1H),7.29-7.35 (m, J=8.5 Hz, 2H), 6.97-7.03 (m, 2H), 6.92-6.97 (m, 2H), 4.90(s, 2H), 4.54 (s, 6H), 3.45 (s, 2H).

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-N-(4-methyl-benzyl)-benzamide(D212)

D212 was prepared using a procedure similar to that of D229. LCMS (m/z)374 (M+H); ¹H NMR (DMSO-d₆) δ: 9.16 (s, 1H), 8.96 (t, J=5.9 Hz, 1H),7.90-7.98 (m, 2H), 7.75 (d, J=7.9 Hz, 1H), 7.17-7.22 (m, 2H), 7.07-7.15(m, 4H), 7.02-7.07 (m, 2H), 4.95 (s, 2H), 4.43 (d, J=6.0 Hz, 2H), 2.27(s, 3H).

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-N-(4-methoxy-benzyl)-benzamide(D213)

D213 was prepared using a procedure similar to that of D229. LCMS (m/z)412 (M+23); ¹H NMR (DMSO-d₆) δ: 9.16 (s, 1H), 8.93 (t, J=6.0 Hz, 1H),7.89-7.98 (m, 2H), 7.75 (d, J=7.9 Hz, 1H), 7.20-7.27 (m, 2H), 7.07-7.12(m, 2H), 7.02-7.07 (m, 2H), 6.86-6.91 (m, 2H), 4.94 (s, 2H), 4.40 (d,J=6.0 Hz, 2H), 3.72 (s, 3H).

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-N-phenyl-benzamide(D214)

D214 was prepared using a procedure similar to that of D229. LCMS (m/z)368 (M+23); ¹H NMR (DMSO-d₆) δ: 10.17 (s, 1H), 7.99 (d, J=8.6 Hz, 2H),7.74 (dd, J=7.8, 4.7 Hz, 3H), 7.32 (t, J=7.8 Hz, 2H), 7.13 (d, J=8.6 Hz,2H), 7.01-7.09 (m, 3H), 4.93 (s, 2H).

N-Cyclopropyl-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide(D215)

D215 was prepared using a procedure similar to that of D229. LCMS (m/z)310 (M+H); ¹H NMR (DMSO-d₆) δ: 9.13 (s, 1H), 8.36 (d, J=4.0 Hz, 1H),7.83 (d, J=8.8 Hz, 2H), 7.66-7.77 (m, 1H), 6.98-7.11 (m, 4H), 4.92 (s,2H), 2.81 (td, J=7.3, 3.7 Hz, 1H), 0.62-0.70 (m, 2H), 0.49-0.57 (m, 2H).

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-N-(tetrahydro-furan-2-ylmethyl)-benzamide(D216)

D216 was prepared using a procedure similar to that of D229. LCMS (m/z)376 (M+23); ¹H NMR (METHANOL-d₄) δ: 8.38 (br. s., 1H), 7.81-7.88 (m,2H), 7.66 (d, J=7.9 Hz, 1H), 6.99-7.07 (m, 4H), 5.02 (s, 2H), 4.10 (qd,J=6.8, 4.8 Hz, 1H), 3.89 (dt, J=8.1, 6.7 Hz, 1H), 3.72-3.79 (m, 1H),3.46-3.54 (m, 1H), 3.37-3.45 (m, 1H), 1.84-2.07 (m, 3H), 1.61-1.70 (m,1H)

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-N-methyl-benzamide(D217)

D217 was prepared using a procedure similar to that of D229. LCMS (m/z)284 (M+H); ¹H NMR (DMSO-d₆) δ: 9.13 (s, 1H), 8.36 (d, J=4.5 Hz, 1H),7.82-7.87 (m, 2H), 7.73 (d, J=7.9 Hz, 1H), 6.99-7.08 (m, 4H), 4.92 (s,2H), 2.75 (d, J=4.5 Hz, 3H).

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-N,N-dimethyl-benzamide(D218)

D218 was prepared using a procedure similar to that of D229. LCMS (m/z)298 (M+H); ¹H NMR (DMSO-d₆) δ: 9.29 (s, 1H), 7.71 (d, J=8.0 Hz, 1H),7.38-7.45 (m, 2H), 6.97-7.05 (m, 4H), 4.91 (s, 2H), 2.92 (br. s., 6H).

N′-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoyl]-hydrazinecarboxylicacid tert-butylester (D219)

D219 was prepared using a procedure similar to that of D229. LCMS (m/z)407 (M+23); ¹H NMR (DMSO-d₆) δ: 10.13 (s, 1H), 9.15 (s, 1H), 8.87 (s,1H), 7.88 (d, J=8.6 Hz, 2H), 7.75 (d, J=8.0 Hz, 1H), 7.02-7.10 (m, 4H),4.93 (s, 2H), 1.41 (s, 9H).

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide (D220)

To a 40 mL scintillation vial containing4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid (77mg, 0.28 mmol, 1.0 eq.) and CDI (101.3 mg, 0.62 mmol), 2.5 eq.) in DMF(3.0 mL) was added Ammonium carbonate (123.3 mg, 1.28 mmol, 4.5 eq.).The mixture was stirred at room temperature overnight. The mixture wastreated with H₂O (5 mL) and the layers were separated. The aqueous wasextracted with EtOAc (2×5 mL), combined organic phase was washed withbrine (10 mL), dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure. The residue was applied to silicachromatography eluting with MeOH/DCM (0:100 to 10:90) to give4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide as awhite solid. LCMS (m/z) 270 (M+H); ¹H NMR (DMSO-d₆) δ: 9.14 (s, 1H),7.87-7.92 (m, 2H), 7.73 (d, J=7.8 Hz, 1H), 7.05 (d, J=8.8 Hz, 4H), 4.93(s, 2H).

5-(4-Hydroxymethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (D221)

To a solution of4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid(200 mg, 0.74 mmol, 1.0 eq.), trimethyl borate (0.5 mL, 4.4 mmol, 6.0eq.) in THF (7.0 mL) was added borane tetrahydrofuran complex solution(1.5 mL, 1.0 M in THF, 1.5 mmol, 2.0 eq.) dropwise under nitrogenatmosphere. The mixture was stirred at room temperature overnight. Themixture was carefully treated with MeOH (2 mL) and poured into EtOAc (10mL) and sat. NaHCO₃ (10 mL). The layers were separated and the aqueousphase was extracted with EtOAc (3×10 mL). Combined organic extracts waswashed with brine (10 mL), dried over MgSO₄, filtered and the filtratewas concentrated under reduced pressure. The residue was applied tosilica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give5-(4-hydroxymethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol as a whitesolid. LCMS (m/z) 279 (M+23); ¹H NMR (DMSO-d₆) δ: 9.09 (s, 1H), 7.70 (d,J=8.0 Hz, 1H), 7.34-7.38 (m, J=8.7 Hz, 2H), 7.01-7.05 (m, 2H), 6.96 (dd,J=8.0, 2.1 Hz, 1H), 6.91-6.93 (m, 1H), 5.18 (t, J=5.7 Hz, 1H), 4.91 (s,2H), 4.49 (d, J=5.7 Hz, 2H).

5-(4-Nitro-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (D222)

To a solution of 1-fluoro-4-nitro-benzene (1.1 mL, 10.0 mmol, 1.0 eq.),2-bromo-5-hydroxy-benzaldehyde (2.0 g, 10.0 mmol, 1.0 eq.) in DMF (30.0mL) was added K₂CO₃ (1.7 g, 12.0 mmol, 1.2 eq.) under nitrogenatmosphere. The mixture was heated at 100° C. overnight. After coolingto room temperature, the mixture was poured into EtOAc (30 mL) and sat.H₂O (30 mL). The layers were separated and the aqueous phase wasextracted with EtOAc (3×20 mL). Combined organic extracts was washedwith brine (30 mL), dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure. The residue was applied to silicachromatography eluting with EtOAc/Heptanes (0:100 to 100:0) to give2-bromo-5-(4-nitro-phenoxy)-benzaldehyde as a yellow fine powder. ¹H NMR(CHLOROFORM-d) δ: 10.31-10.37 (m, 10H), 8.26 (dd, J=9.0, 0.3 Hz, 15H),8.21-8.28 (m, 13H), 7.73 (d, J=8.6 Hz, 3H), 7.73 (dt, J=8.7, 0.5 Hz,7H), 7.62 (dd, J=3.1, 0.3 Hz, 10H), 7.20-7.29 (m, 19H), 7.00-7.10 (m,23H). Amount obtained, 2.6 g, 80.7% yield.

To a solution of 2-Bromo-5-(4-nitro-phenoxy)-benzaldehyde (966 mg, 3.0mmol, 1.0 eq.) in 1,4-dioxane (25 mL) was added bis-pinacol-diboron (838mg, 3.3 mmol, 1.1 eq.), KOAc (883 mg, 9.0 mmol, 3.0 eq.) andPdCl₂(dppf)₂ (66 mg, 0.09 mmol, 0.03 eq.). The mixture was degassed withN₂ and heated at 80° C. overnight. After cooling to room temperature,the mixture was filtered though a short pack of celite and the filtratewas concentrated under reduced pressure. The residue was applied tosilica chromatography eluting with EtOAc/Heptanes (0:100 to 100:0) togive5-(4-nitro-phenoxy)-2-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehydeas a yellow solid. ¹H NMR (CHLOROFORM-d) δ: 10.65 (s, 1H), 8.19-8.29 (m,J=9.3 Hz, 2H), 8.01 (d, J=8.2 Hz, 1H), 7.66 (d, J=2.5 Hz, 1H), 7.32 (dd,J=8.2, 2.5 Hz, 1H), 7.04-7.10 (m, 2H), 1.41 (s, 12H). Amount obtained,724 mg, 65.3% yield.

To a suspension of5-(4-nitro-phenoxy)-2-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde(721 mg, 1.9 mmol, 1.0 eq.) in EtOH (15 mL) at 0° C. was added NaBH₄(73.8 mg, 1.9 mmol, 1.0 eq.) in small portions. The mixture was stirredat 0° C. for 20 minutes and allowed to warm to room temperature inanother 1 h. After cooling to 0° C., the clear solution was carefullytreated with H₂O (1 mL), followed by slow addition of HCl (5 mL, 3N).The resulting yellow suspension was allowed to ward to room temperaturegradually and stirred for 2 h. The mixture was then treated with sat.NaHCO₃ drop wise until PH reaching 7. The precipitate was collected byfiltration, washed with H₂O to give5-(4-nitro-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol as a white powder.LCMS (m/z) 294 (M+23); ¹H NMR (DMSO-d₆) δ: 7.26 (d, J=8.6 Hz, 1H), 6.93(d, J=3.0 Hz, 1H), 6.56 (dd, J=8.5, 3.0 Hz, 1H), 4.37 (s, 2H). Amountobtained, 510 mg, 96.4% yield.

5-(4-Amino-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (D223)

To a 25 mL round-bottom flask fitted with magnetic stirring bar wasadded 5-(4-nitro-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (310 mg, 1.1mmol, 1.0 eq.), followed by addition of MeOH (10 mL). The flask wasevacuated and recharged with N₂ twice. To the stirring solution wasadded 5% Pd/C (60 mg) and the flask was evacuated and recharged with H₂three times. The resulting suspension was stirred under a H₂ balloon atroom temperature overnight. The mixture was filtered through a shortpack of celite and washed with MeOH (3×10 mL). The combined filtrate wasconcentrated under reduced pressure to give a light yellow oil. The oilwas dissolved in minimum amount of MeOH and carefully treated with HCl(conc.). The precipitate was collected by filtration, washed withheptanes to give 5-(4-amino-phenoxy)-3H-benzo[c][1,2]oxaborol-1-olhydrochloride salt as a white solid. LCMS (m/z) 242 (M+H); ¹H NMR(DMSO-d₆) δ: 9.03 (br. s., 1H), 7.64 (d, J=8.0 Hz, 1H), 6.77-6.89 (m,4H), 6.64-6.77 (m, 2H), 4.86 (s, 2H), 3.30 (br. s., 2H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-acetamide(D224)

To a 20 mL scintillation vial containing5-(4-amino-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (68 mg, 0.28 mmol, 1.0eq.) in DCM (3.0 mL) was added Et₃N (47 μL, 0.33 mmol, 1.2 eq.),followed by acetyl chloride (22 μL, 0.31 mmol, 1.1 eq.). The mixture wasstirred at room temperature overnight. The mixture was concentratedunder reduced pressure. The residue was applied to silica chromatographyeluting with MeOH/DCM (0:100 to 10:90) to giveN-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-acetamideas a white solid. LCMS (m/z) 284 (M+H); ¹H NMR (DMSO-d₆) δ: 10.17 (s,1H), 7.68 (d, J=8.1 Hz, 1H), 7.58-7.63 (m, 2H), 6.94-6.99 (m, 2H), 6.88(dd, J=8.0, 2.1 Hz, 1H), 6.84 (d, J=1.5 Hz, 1H), 4.85 (s, 2H), 3.12 (s,1H), 2.00 (s, 3H).

N-[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-methanesulfonamide(D225)

To a 20 mL scintillation vial containing5-(4-amino-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (50 mg, 0.21 mmol, 1.0eq.) in DCM (3.0 mL) was added Et₃N (35 μL, 0.25 mmol, 1.2 eq.),followed by methanesulfonyl chloride (18 μL, 0.31 mmol, 1.1 eq.). Themixture was stirred at room temperature overnight. The mixture wasconcentrated under reduced pressure. The residue was applied to silicachromatography eluting with MeOH/DCM (0:100 to 10:90) to giveN-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-methanesulfonamideas a white solid. LCMS (m/z) 342 (M+23); ¹H NMR (DMSO-d₆) δ: 9.72 (s,1H), 7.65-7.79 (m, 1H), 7.21-7.26 (m, 2H), 7.01-7.05 (m, 2H), 6.91-6.94(m, 1H), 6.89-6.91 (m, 1H), 4.88 (s, 2H), 2.94 (s, 3H).

4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid(D226)

To a 250 mL round-bottom flask equipped with magnetic stirring barcontaining4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile(5.0 g, 20.0 mmol, 1.0 eq.), MeOH (90 mL) and 1,4-dioxane (50 mL) wasslowly added NaOH (6N, 20 mL). The flask was fitted with a air condenserand heated in a preheated 90° C. oil bath for 2 days. The flask was thenimmersed in an ice-bath and the solution was carefully treated with HCl(1N) until the PH value reached 2. The mixture was extracted with EtOAc(3×150 mL). Combined organic extracts was washed with H₂O (200 mL) andbrine (200 mL), dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure to give4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid asa white solid. LCMS (m/z) 271 (M+H); ¹H NMR (DMSO-d₆) δ: 12.80 (br. s.,1H), 9.16 (s, 1H), 7.94 (d, J=8.6 Hz, 2H), 7.76 (d, J=8.0 Hz, 1H),7.01-7.15 (m, 4H), 4.94 (s, 2H). Amount obtained, 4.7 g, 87.0% yield.

[4-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-morpholin-4-yl-methanone(D227)

D227 was prepared using a procedure similar to that of D229. LCMS (m/z)701 (2M+23); ¹H NMR (DMSO-d₆) δ: 9.15 (s, 1H), 7.75 (d, J=7.9 Hz, 1H),7.42-7.49 (m, 2H), 7.06-7.10 (m, 3H), 7.02-7.06 (m, 1H), 4.95 (s, 2H),3.40-3.65 (m, 8H).

N-Cyclopentyl-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide(D228)

D228 was prepared using a procedure similar to that of D229. LCMS (m/z)352 (M+H); ¹H NMR (DMSO-d₆) δ: 9.15 (s, 1H), 8.15 (d, J=7.9 Hz, 1H),7.86-7.92 (m, 2H), 7.75 (d, J=8.5 Hz, 1H), 7.05-7.11 (m, 2H), 7.00-7.05(m, 2H), 4.94 (s, 2H), 3.69-3.81 (m, 1H), 1.77-1.86 (m, 2H), 1.67-1.77(m, 2H), 1.56-1.65 (m, 1H), 1.22-1.37 (m, 4H), 1.04-1.20 (m, 1H).

N-Benzyl-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide(D229)

To a 40 mL scintillation vial containing4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid(150 mg, 0.55 mmol, 1.0 eq.), EDCI (157.2 mg, 0.82 mmol, 1.5 eq.), HOBt(111.5 mg, 0.82 mmol, 1.5 eq.) and DMAP (12 mg, 0.1 mmol, 0.2 eq.) inDCM (10.0 mL) was added benzylamine (24 μL, 2.2 mmol, 4.0 eq.) dropwise. The mixture was stirred at room temperature overnight. The mixturewas treated with H₂O (10 mL) and the layers were separated. The aqueouswas extracted with DCM (2×5 mL), combined organic phase was washed withbrine (10 mL), dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure. The residue was applied to silicachromatography eluting with MeOH/DCM (0:100 to 10:90) to giveN-benzyl-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamideas a white solid. LCMS (m/z) 360 (M+H); ¹H NMR (DMSO-d₆) δ: 9.01 (t,J=6.0 Hz, 1H), 7.91-8.00 (m, 2H), 7.76 (d, J=7.9 Hz, 1H), 7.29-7.36 (m,5H), 7.21-7.27 (m, 1H), 7.08-7.13 (m, 2H), 7.02-7.07 (m, 2H), 4.95 (s,2H), 4.48 (d, J=6.0 Hz, 2H).

Example 20 In Vitro Assays

The ability of the compounds described herein to inhibitpro-inflammatory cytokines or phosphodiesterases were tested.

Cytokine Assay

Frozen human peripheral blood mononucleocytes (PBMC) were thawed andcentrifuged. Cryopreservation media was aspirated off of the cellpellet, and the cells were resuspended in fresh culture media (CM)comprising RPMI 1640 and 10% FBS in 96 well plates. Test article wasdissolved in DMSO to form a 10 mM sample (DMSO, 100%). The 10 mM sampleswere diluted to 100 μM in CM (DMSO, 1%), then further diluted to 10, 1,0.1, 0.01 μM in 200 μL of CM (n=3). Inducer (1 μg/mL LPS for TNF-α andIL-1β [and IL-6] or 20 ug/mL PHA for IFNγ, IL-2, IL-4, IL-5 and IL-10.IL-23 was induced with 100 ng/ml IFN-g+1 mg/ml LPS, using THP-1 cells.Vehicle (1% DMSO) was used as a control for this experiment. Vehiclewithout inducer was used as a negative control. Cells were incubated at37° C., 5% CO₂. Supernatants were extracted at 24 hours (for TNF-α,IL-1β, IL-2, IL-6 and IFNγ) and 48 hours (for IL-4, IL-5, IL-10 andIL-23), and stored at −20° C. Supernatants were thawed and assayed forcytokine expression using the fluorochrome-labeled cytokine-specificbeads and a BD FACSArray™. IL-23 was assayed using a commercial ELISAkit (R&D Systems).

IC50 (μM) or inhibition % at 10 μM Cmpd TNF-α IL-2 IFN-γ IL-5 IL-10C7 + + + + + C17 ++++ ++++ ++++ +++ ++ C18 + + + + + C23 ++ ++ ++ ++ ++C24 + + + + + C25 +++ ++++ +++ ++ +++ C26 ++++ ++++ ++++ ++++ ++++C31 + + {circumflex over ( )}{circumflex over ( )} + + C36 + +++ + ++ +C37 ++ +++ +++ ++ ++ C38 + + + + + C100 + + + + + D1 ++ +++ +++ +++ + D2++++ ++++ ++++ ++++ + D3 ++++ ++++ ++++ ++++ + D4 ++++ ++++ ++++ ++++ +D5 ++++ +++ ++++ ++++ + D6 ++++ ++++ ++++ ++ ++ D7 ++++ ++++ ++++ ++++++++ D8 + +++ + + + D9 ++++ ++++ ++++ ++++ ++++ D10 ++++ ++ ++ ++ +++D11 ++++ +++ +++ ++ +++ D12 ++++ ++++ ++++ +++ ++++ D13 ++ +++ +++ ++++++ D14 ++++ ++++ ++++ ++++ +++ D15 ++++ ++++ ++++ D16 ++++ +++ ++++ D17++ + + D18 + + + D19 +++ +++ +++ D20 ++++ ++++ ++++ D21 +++ ++++ ++++D22 ++++ ++++ ++++ D23 ++ D24 +++ D25 ++ ++++ +++ ++++ +++ D26 + +++ ++++ + D27 ++++ ++++ ++++ D28 ++++ ++++ ++++ ++++ +++ D29 ++++ ++++ ++++++++ + D30 ++++ ++++ ++++ ++++ ++++ D31 +++ D32 ++++ ++++ ++++ ++++ ++++D33 ++++ ++++ ++++ ++++ ++++ D34 +++ ++++ ++++ +++ +++ D35 ++++ ++++++++ D36 + + + D37 ++++ ++++ ++++ ++++ ++++ D38 ++++ ++++ ++++ ++++ +++D39 {circumflex over ( )}{circumflex over ( )} {circumflex over( )}{circumflex over ( )} {circumflex over ( )}{circumflex over ( )}{circumflex over ( )} D40 ++++ ++++ ++++ ++++ ++++ D41 +++ ++++ ++++ ++++++ D42 {circumflex over ( )}{circumflex over ( )}{circumflex over ( )}{circumflex over ( )}{circumflex over ( )}{circumflex over( )}{circumflex over ( )} {circumflex over ( )}{circumflex over( )}{circumflex over ( )}{circumflex over ( )} {circumflex over( )}{circumflex over ( )}{circumflex over ( )} {circumflex over( )}{circumflex over ( )}{circumflex over ( )} D43 {circumflex over ( )}{circumflex over ( )}{circumflex over ( )}{circumflex over( )}{circumflex over ( )} {circumflex over ( )}{circumflex over( )}{circumflex over ( )} {circumflex over ( )}{circumflex over( )}{circumflex over ( )} {circumflex over ( )}{circumflex over( )}{circumflex over ( )} D44 ++++ ++++ ++++ D45 ++++ ++++ ++++ D46 ++++++++ ++++ ++++ ++++ D47 ++++ ++++ ++++ ++++ +++ D48 ++++ ++++ ++++ D49++ ++ ++ D50 ++++ ++++ ++++ +++ ++ D51 +++ +++ +++ ++ +++ D52 + ++++ + + D53 ++++ ++++ ++++ +++ +++ D54 ++++ ++++ ++++ +++ ++++ D55 ++++++ ++++ +++ ++ D56 + ++ + + + D57 ++ ++++ +++ ++++ + D58 +++ ++++ ++++++++ + D59 {circumflex over ( )}{circumflex over ( )} {circumflex over( )}{circumflex over ( )}{circumflex over ( )} {circumflex over( )}{circumflex over ( )} {circumflex over ( )} D60 ++++ ++++ ++++ ++++++++ D61 {circumflex over ( )} {circumflex over ( )} {circumflex over( )}{circumflex over ( )} {circumflex over ( )} D62 ++++ ++++ ++++ ++++++ D63 ++++ ++++ +++ +++ +++ D64 +++ ++ ++ + ++ D65 ++++ ++++ ++++ ++++++++ D66 ++++ ++++ ++++ ++++ ++++ D67 ++++ ++++ ++++ ++++ ++++ D68 ++++++++ ++ +++ +++ D69 +++ +++ +++ D70 +++ ++++ +++ D71 +++ +++ +++ ++ +D72 +++ +++ +++ ++ + D73 +++ +++ ++ +++ + D74 +++ ++++ ++++ +++ +++ D75+++ +++ ++ ++ + D76 +++ ++++ +++ ++ +++ D77 + +++ +++ + ++ D78 +++ ++++++ +++ +++ D79 + + + + + D80 + + + + + D81 + + + ++ + D82 ++++ ++++++++ +++ ++++ D84 +++ +++ ++ ++ +++ D85 ++++ ++++ ++++ ++++ +++ D86 ++++++++ ++++ ++++ ++++ D87 {circumflex over ( )}{circumflex over ( )}{circumflex over ( )} {circumflex over ( )}{circumflex over ( )}{circumflex over ( )} D88 {circumflex over ( )} {circumflex over( )}{circumflex over ( )}{circumflex over ( )} {circumflex over ( )}{circumflex over ( )}{circumflex over ( )} {circumflex over( )}{circumflex over ( )} D89 {circumflex over ( )}{circumflex over ( )}{circumflex over ( )}{circumflex over ( )} {circumflex over ( )}{circumflex over ( )} D90 ++ +++ +++ {circumflex over ( )} {circumflexover ( )}{circumflex over ( )} D91 {circumflex over ( )} {circumflexover ( )} D92 {circumflex over ( )} {circumflex over ( )}{circumflexover ( )} {circumflex over ( )} {circumflex over ( )} {circumflex over( )} D93 {circumflex over ( )} {circumflex over ( )}{circumflex over( )} {circumflex over ( )}{circumflex over ( )} {circumflex over ( )}{circumflex over ( )} D94 +++ +++ +++ +++ + D95 ++++ ++++ ++++ ++++ +++D96 ++++ ++++ ++++ +++ +++ D97 ++++ ++++ ++++ ++++ ++++ D98 ++++ ++++++++ ++++ ++++ D99 ++++ ++++ ++++ ++++ ++++ D100 ++++ ++++ ++++ ++++++++ D101 ++++ ++++ ++++ ++++ +++ D102 ++++ ++++ ++++ ++++ +++ D103 +++++++ ++++ ++++ +++ D104 +++ +++ +++ ++ ++ D105 +++ +++ +++ ++ +++ D106++++ ++++ ++++ ++++ ++ D107 ++++ ++++ ++++ ++++ ++++ D109 ++++ ++++ ++++++++ ++++ D110 ++++ ++++ ++++ ++++ + D111 ++++ D112 ++++ ++++ ++++ +++++++ D113 ++++ ++++ ++++ ++++ ++ D114 ++++ ++++ ++++ ++++ + D115 ++++++++ ++++ ++++ ++ D116 ++++ ++++ ++++ ++++ +++ D117 +++ +++ + +++ + D118++++ ++++ ++++ ++++ +++ D119 ++++ ++++ ++++ ++++ ++++ D120 ++++ ++++++++ ++++ ++++ D121 ++++ ++++ ++++ ++++ +++ D122 ++++ ++++ ++++ ++++++++ D123 ++++ ++++ ++++ +++ +++ D124 ++++ ++++ ++++ ++++ ++++ D125 ++++++++ ++++ ++++ ++++ D126 ++++ ++++ ++++ ++++ ++++ D127 ++++ ++++ ++++++++ ++++ D128 ++++ ++++ ++++ ++++ ++++ D129 ++++ D130 ++++ ++++ ++++++++ ++++ D131 ++++ ++++ ++++ ++++ ++++ D132 ++++ ++++ ++++ ++++ ++++D133 ++++ D134 ++++ D135 ++++ D136 ++++ D137 +++ {circumflex over( )}{circumflex over ( )}{circumflex over ( )} {circumflex over( )}{circumflex over ( )}{circumflex over ( )} {circumflex over( )}{circumflex over ( )} {circumflex over ( )}{circumflex over ( )}D138 +++ {circumflex over ( )}{circumflex over ( )}{circumflex over ( )}{circumflex over ( )}{circumflex over ( )} {circumflex over( )}{circumflex over ( )}{circumflex over ( )} {circumflex over( )}{circumflex over ( )} Rolipram ++++ ++++ ++++ ++++ ++++ wherein{circumflex over ( )} is <30%, {circumflex over ( )}{circumflex over( )} is 30 to <60%, {circumflex over ( )}{circumflex over( )}{circumflex over ( )} is 60 to <90%, {circumflex over( )}{circumflex over ( )}{circumflex over ( )}{circumflex over ( )} is90 to 100%. wherein ++++ is <1 μM, +++ is 1 to <4 μM, ++ is 4 to 10μM, + is >10 μM.

PDE Isoform Profiling

Recombinant human PDE enzymes were expressed in a baculoviral system.The assay is a modification of the 2-step method of Thompson & Appleman(Biochem. 10:311-316, 1971), which was adapted for 96-well plate format.Stock solutions were prepared at 40 mM in 100% DMSO. Final [DMSO] was5%. Each compound was tested by performing 1 in 4 serial dilutions atstarting concentration of 100 mM. Each concentration was tested induplicate. IC50s were generated from 11-point curves and analyzed usingPrism software (GraphPad Inc.). PDE isoforms tested include PDE1A3(cAMP), PDE1A3 (cGMP), PDE2A3, PDE3Cat, PDE4Cat, PDE4A4, PDE4B2, PDE4C2,PDE4D3, PDE5Cat, PDE6AB, PDE7A1, PDE8A1, PDE9A1, PDE10A1 (cAMP), PDE10A1(cGMP), PDE11A1 (cAMP) and PDE11A1 (cGMP).

PDE4 Assay

PDE4 partially purified from human U-937 myeloid leukemia cells wasused. Test article and/or vehicle was incubated with 0.2 mg enzyme and 1mM cAMP containing 0.01 mM [3H]cAMP in Tris buffer pH 7.5 for 20 minutesat 25° C. The reaction was terminated by boiling for 2 minutes and theresulting AMP is converted to adenosine by addition of 10 mg/ml snakevenom nucleotidase and further incubation at 37° C. for 10 minutes.Unhydrolyzed cAMP is bound to AG1-X2 resin, and remaining [3H]Adenosinein the aqueous phase is quantitated by scintillation counting. Testarticles were tested at 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, and 0.001μM for IC₅₀ determination.

Cmpd PDE4 C17 ++++ C18 + C23 +++ C24 ++ C25 +++ C26 ++++ C31 ++ C36 ++C37 ++ C38 ++ C100 + D1 +++ D2 ++++ D3 ++++ D4 ++++ D5 ++++ D6 ++++ D7++++ D9 ++++ D10 +++ D11 ++++ D12 ++++ D13 +++ D14 ++++ D15 ++++ D16++++ D17 ++++ D19 ++++ D20 ++++ D21 ++++ D22 ++++ D25 ++++ D26 +++ D27++++ D28 ++++ D29 ++++ D30 ++++ D32 ++++ D33 ++++ D34 +++ D35 ++++ D37++++ D38 ++++ D40 ++++ D41 ++++ D44 ++++ D45 ++++ D46 ++++ D47 ++++ D48++++ D49 +++ D50 ++++ D51 ++++ D52 +++ D53 ++++ D54 ++++ D55 ++++ D56+++ D57 ++++ D58 ++++ D59 + D60 ++++ D62 +++ D63 ++++ D65 ++++ D66 ++++D67 ++++ D68 ++++ D69 ++++ D70 +++ D71 ++++ D72 ++++ D73 ++++ D74 ++++D76 ++++ D78 ++++ D82 ++++ D84 ++++ D85 ++++ D86 ++++ D87 ++ D88 +++ D89+++ D90 ++++ D91 + D92 +++ D93 +++ D94 ++++ D95 ++++ D96 ++++ D97 ++++D98 ++++ D99 ++++ D100 ++++ D101 ++++ D102 ++++ D103 +++ D104 ++++ D105+++ D106 ++++ D107 ++++ D108 ++ D109 ++++ D110 ++++ D111 ++++ D112 ++++D113 ++++ D114 ++++ D115 ++++ D116 ++++ D117 ++++ D118 ++++ D119 ++++D120 ++++ D122 ++++ D123 ++++ D124 ++++ D125 ++++ D126 ++++ D127 ++++D128 ++++ D129 ++++ D130 ++++ D131 ++++ D132 ++++ D133 ++++ D134 ++++D135 ++++ D136 ++++ Rolipram ++++ wherein ++++ is <1 μM, +++ is 1 to <4μM, ++ is 4 to 10 μM, + is >10 μM.

Example 21 In Vivo Assays 1. In Vivo Anti-Inflammation Activity inPhorbol Ester Induced Mouse Ear Edema Model

Phorbol 12-myristate 13-acetate (PMA, 5 μg in 20 μL of acetone) wasapplied topically to the anterior and posterior surfaces of the rightear to eight groups of CD-1 (Crl.) derived male mice of 5 each (weighing22±2 g). Test substances and vehicle (acetone:ethanol/1:1, 20 μL/ear)were each applied to both ears topically 30 minutes before and 15minutes after PMA challenge. Dexamethasone (1 mg/ear×2) used as thepositive control was administered topically to test animals using thesame application schedule. Ear swelling was then measured by a Dyermodel micrometer gauge at 6 hours after PMA application as an index ofinflammation. Percent inhibition was calculated according to theformula: [(Ic−It)/Ic]×100%, where Ic and It refer to increase of earthickness (mm) in control and treated mice, respectively. Percentinhibition of 30 percent or more in ear swelling was consideredsignificant anti-inflammatory activity.

Dose % inhi- Compound Vehicle 20 μL/ear × 2 bition C17 1 mg/ear × 2 ***C26 1 mg/ear × 2 *** C27 3 mg/ear × 2 *** C27 1 mg/ear × 2 *** D4Acetone:Ethanol/1:1 1 mg/ear × 2 ** D4 Acetone:Ethano/1:1 1 mg/ear × 2*** D5 Acetone:Ethanol/1:1 1 mg/ear × 2 ** D6 Acetone:Ethanol/1:1 1mg/ear × 2 ** D6 Acetone:Ethanol/1:1 0.2 mg/ear × 2 * D7Acetone:Ethanol/1:1 1 mg/kg × 2 * D10 Acetone:Ethanol/1:1 1 mg/ear × 2*** D12 Acetone:Ethanol/1:1 1 mg/ear × 2 ** D12 Acetone:Ethanol/1:1 0.2mg/ear × 2 * D14 Acetone:Ethanol/1:1 1 mg/ear × 2 * D14 95% Ethanol 0.05mg/ear × 2 * D14 95% Ethanol 0.17 mg/ear × 2 * D14 95% Ethanol 0.51mg/ear × 2 * D14 95% Ethanol 1 mg/ear × 2 * D15 Acetone:Ethanol/1:1 1mg/ear × 2 ** D16 Acetone:Ethano/1:1 1 mg/ear × 2 **** D16Acetone:Ethano/1:1 0.2 mg/ear × 2 *** D24 Acetone:Ethano/1:1 1 mg/ear ×2 *** D29 Acetone:Ethanol/1:1 1 mg/ear × 2 * D31 Acetone:Ethanol/1:1 1mg/ear × 2 ** D32 Acetone:Ethanol/1:1 1 mg/ear * D32 Acetone:Ethanol/1:11 mg/ear × 2 * D33 Acetone:Ethanol/1:1 1 mg/ear * D34Acetone:Ethanol/1:1 1 mg/ear * D37 Acetone:Ethanol/1:1 1 mg/ear × 2 ***D37 95% Ethanol 3 mg/ear × 2 *** D46 Acetone:Ethano/1:1 1 mg/ear × 2 ***D46 Acetone:Ethanol/1:1 1 mg/ear × 2 *** D46 Acetone:Ethanol/1:1 0.2mg/ear × 2 * D46 Acetone:Ethanol/1:1 0.1 mg/ear × 2 * D46 95% Ethanol0.05 mg/ear × 2 * D46 95% Ethanol 0.17 mg/ear × 2 * D46 95% Ethanol 0.5mg/ear × 2 * D46 95% Ethanol 3 mg/ear × 2 *** D48 Acetone:Ethanol/1:1 1mg/ear × 2 * D48 Acetone:Ethanol/1:1 0.2 mg/ear × 2 * D50Acetone:Ethano/1:1 1 mg/ear × 2 *** D60 Acetone:Ethanol/1:1 1 mg/ear × 2** D60 Acetone:Ethanol/1:1 0.2 mg/ear × 2 * D60 Acetone:Ethanol/1:1 0.1mg/ear × 2 * D61 Acetone:Ethanol/1:1 1 mg/ear × 2 ** D61Acetone:Ethanol/1:1 0.2 mg/ear × 2 * D61 Acetone:Ethanol/1:1 0.1 mg/ear× 2 * D63 Acetone:Ethano/1:1 1 mg/ear × 2 * D65 Acetone:Ethano/1:1 1mg/ear × 2 ** D67 Acetone:Ethanol/1:1 1 mg/ear × 2 *** D68Acetone:Ethanol/1:1 1 mg/ear × 2 ** D69 1 mg/ear × 2 ** D73 3 mg/ear × 2*** D73 1 mg/ear × 2 ** D86 95% Ethanol 0.063 mg/ear × 2 * D86 95%Ethanol 0.21 mg/ear × 2 * D86 95% Ethanol 0.63 mg/ear × 2 * D86 95%Ethanol 3 mg/ear × 2 * D90 95% EthanolAcetone:1/1 1 mg/ear × 2 *** D9595% Ethanol 0.02 mg/ear × 2 * D95 95% Ethanol 0.06 mg/ear × 2 * D95 95%Ethanol 0.2 mg/ear × 2 * D97 95% Ethanol 0.056 mg/ear × 2 * D97 95%Ethanol 0.19 mg/ear × 2 * D97 95% Ethanol 0.56 mg/ear × 2 ** D98 95%Ethanol 0.02 mg/ear × 2 * D98 95% Ethanol 0.06 mg/ear × 2 * D98 95%Ethanol 0.2 mg/ear × 2 ** D99 95% Ethanol 0.02 mg/ear × 2 * D99 95%Ethanol 0.067 mg/ear × 2 * D99 95% Ethanol 0.2 mg/ear × 2 * D99 95%Ethanol 3 mg/ear × 2 *** D100 95% Ethanol 0.028 mg/ear × 2 * D100 95%Ethanol 0.093 mg/ear × 2 * D100 95% Ethanol 0.28 mg/ear × 2 ** D101 95%Ethanol 0.8 mg/ear × 2 * D101 95% Ethanol 2.4 mg/ear × 2 * D102 95%Ethanol 0.02 mg/ear × 2 * D102 95% Ethanol 0.067 mg/ear × 2 * D102 95%Ethanol 0.2 mg/ear × 2 * D102 95% Ethanol 3 mg/ear × 2 ** D102 95%Ethanol 1 mg/ear × 2 ** D107 95% Ethanol 0.24 mg/ear × 2 ** D107 95%Ethanol 0.8 mg/ear × 2 *** D107 95% Ethanol 2.4 mg/ear × 2 *** D107 95%Ethanol 0.24 mg/ear × 2 * D107 95% Ethanol 0.02 mg/ear × 2 * D107 95%Ethanol 0.067 mg/ear × 2 ** D107 95% Ethanol 0.2 mg/ear × 2 *** D107 95%Ethanol 0.02 mg/ear × 2 * D107 95% Ethanol 0.06 mg/ear × 2 * D109 95%Ethanol 0.02 mg/ear × 2 * D109 95% Ethanol 0.067 mg/ear × 2 * D109 95%Ethanol 0.2 mg/ear × 2 * D110 95% Ethanol 0.02 mg/ear × 2 * D110 95%Ethanol 0.06 mg/ear × 2 * D110 95% Ethanol 0.2 mg/ear × 2 * D111 95%Ethanol 0.015 mg/ear × 2 * D111 95% Ethanol 0.05 mg/ear × 2 * D111 95%Ethanol 0.15 mg/ear × 2 * D111 95% Ethanol 1 mg/ear × 2 * D124 95%Ethanol 1 mg/ear × 2 * Dexamethasone 1 mg/ear × 2 *** wherein * is <30%,** is 30 to <60%, *** is 60 to <90%, **** is 90 to 100%.

2. In Vivo Anti-Inflammation Activity in Oxazolone Induced Mouse EarEdema Model

Groups of 5 BALB/c male mice weighing 23±2 g were used. The preshavedabdomens of test animals were sensitized by application of 100 μL of1.5% oxazolone solution dissolved in acetone. Seven days after theinitial sensitization, test substances, as well as vehicle(acetone:ethanol/1:1, 20 μL/ear) were each administered topically to theanterior and posterior surfaces of the right ear 30 minutes before, and15 minutes after, challenge by a second application of oxazolone (1% inacetone, 20 ml/ear) via topical route. As a positive control,indomethacin (0.3 mg/ear×2) was administered topically using the sametreatment regime as for the test compounds. Twenty-four hours after thesecond application of oxazolone, the ear thickness of each mouse wasmeasured with a Dyer model micrometer gauge. A 30 percent or moreinhibition in ear swelling relative to the vehicle control wasconsidered significant and indicated possible anti-inflammatoryactivity.

Dose % inhi- Compound Vehicle 20 μL/ear × 2 bition C27 3 mg/ear × 2 ****D4 Acetone:Ethanol/1:1 1 mg/ear × 2 *** D4 Acetone:Ethanol/1:1 0.02mg/ear × 2 * D5 Acetone:Ethanol/1:1 1 mg/ear × 2 *** D6Acetone:Ethanol/1:1 1 mg/ear × 2 * D6 Acetone:Ethanol/1:1 0.2 mg/ear ×2 * D7 Acetone:Ethanol/1:1 1 mg/kg × 2 * D12 Acetone:Ethanol/1:1 1mg/ear × 2 *** D12 Acetone:Ethanol/1:1 0.2 mg/ear × 2 * D15Acetone:Ethanol/1:1 1 mg/ear × 2 **** D16 95% Ethanol 3 mg/ear × 2 * D2295% Ethanol 3 mg/ear × 2 * D27 95% Ethanol 3 mg/ear × 2 ** D37Acetone:Ethanol/1:1 1 mg/ear × 2 * D46 Acetone:Ethanol/1:1 1 mg/ear ×2 * D48 Acetone:Ethanol/1:1 1 mg/ear × 2 ** D48 Acetone:Ethanol/1:1 0.2mg/ear × 2 * D60 Acetone:Ethanol/1:1 1 mg/ear × 2 * D60Acetone:Ethanol/1:1 0.2 mg/ear × 2 * D60 Acetone:Ethanol/1:1 0.1 mg/ear× 2 * D61 Acetone:Ethanol/1:1 1 mg/ear × 2 * D61 Acetone:Ethanol/1:1 0.2mg/ear × 2 * D61 Acetone:Ethanol/1:1 0.1 mg/ear × 2 * D67Acetone:Ethanol/1:1 1 mg/ear × 2 * D68 Acetone:Ethanol/1:1 1 mg/ear ×2 * D96 Acetone:Ethanol/1:1 1 mg/ear × 2 * D97 95% Ethanol 0.56 mg/ear ×2 * D99 95% Ethanol 0.02 mg/ear × 2 * D99 Acetone:Ethanol/1:1 1 mg/ear ×2 * D102 Acetone:Ethanol/1:1 1 mg/ear × 2 * D107 95% Ethanol 2.4 mg/ear× 2 * D111 95% Ethanol 0.15 mg/ear × 2 * D122 Acetone:Ethanol/1:1 1mg/ear × 2 * D124 Acetone:Ethanol/1:1 1 mg/ear × 2 * Indomethacin 95%Ethanol 0.3 mg/ear × 2 **** wherein * is <20%, ** is 20 to <30%, *** is30 to <40%, **** is 40 to 60%.

Example 22 Preclinical Toxicology of C17, a Novel Oxaborole inDevelopment for the Topical Treatment of Psoriasis

C17 (5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole) is anovel oxaborole compound with anti-inflammatory activity. Preclinicaltoxicity data is available for in vitro studies and in vivo studiesfollowing systemic and topical administration to shrews, ferrets, rats,and mice. C17 (1 μM) was classified as a low potency hERG-channelblocker, minimizing concerns over cardiovascular safety. C17 (up to 5000μg per plate) demonstrated no mutagenic activity in the presence orabsence of Aroclor-induced S9 liver fraction against Salmonellatyphimurium strains TA98, TA100, TA1535, and TA1537 and Escherichia colistrain WP2 uvrA. C17 (up to 500 μg/mL), demonstrated no clastogenicactivity in the In Vitro Mammalian Chromosome Aberration Assay in thepresence or absence of Aroclor-induced S9 using human peripheral bloodlymphocytes. Following oral administration of 10, 30, and 100 mg/kg toshrews, (Suncus murinus), dose-responsive emetic effect was observed.The no-observed-effect level (NOEL) was 10 mg/kg, and was associatedwith significant plasma exposure. Following oral administration of 10,30, and 100 mg/kg to ferrets, no emetic episodes were observed in anydose group. Following oral administration of 30, 100, and 300 mg/kg/dayto male and female Sprague-Dawley rats for 14 consecutive days, the NOELwas determined to be 300 mg/kg/day. No mortality, adverse effects onclinical pathology, or microscopic or macroscopic changes were observedin any dose group. C17 was formulated as a 1%, 5%, and 10% solution inacetone/ethanol (50:50, v/v) and tested in a local lymph node assay forits potential to induce a hypersensitivity response. Topical treatmentwith C17 to female CBA/J mice did not result in a stimulation index of 3or greater and therefore C17 was not considered to have skin sensitizingactivity. C17 is a novel compound in development for the topicaltreatment of psoriasis and has been demonstrated to be safe in variouspreclinical toxicity studies.

Example 23 In Vitro Activity and Mechanism of Action of C17, a NovelOxaborole in Development for Treatment of Psoriasis

C17 (4-cyanophenoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole) is a broadspectrum anti-inflammatory compound currently under development for thetopical treatment of plaque psoriasis. C17 inhibits TNF-α secretion fromperipheral blood mononuclear cells (PBMCs) stimulated bylipopolysaccharide (LPS) and IL-2 and IFN-γ secretion after stimulationwith phytohemagglutinin (PHA) in the nanomolar range. C17 inhibits TNF-αsecretion with an IC₅₀ of 770 nM; however the pro-inflammatory cytokinesIL-1 and IL-6 are not affected by C17. IL-2 and IFN-γ are inhibited withIC₅₀s of 460 nM and 270 nM respectively. IL-5 and IL-10 are inhibited byC17 in the low micromolar range. One mechanism of action of C17 toinhibit a broad range of cytokine secretion may be through inhibition ofphosphodiesterase 4 (PDE4). C17 inhibits PDE4 enzyme activity in humanU937 cells with an IC₅₀ of 0.49 μM, inhibiting all four PDE4 isoformsequally. C17 has been shown to be a competitive inhibitor of thesubstrate cAMP, as determined by enzyme kinetic analysis. C17 alsoinhibits PDE7 with an IC₅₀ of 0.73 μM but does not significantly inhibitPDE1, 2, 3, or 5. In contrast to classic PDE4 inhibitors, for exampleRolipram, C17 inhibits production of IL-23 from human THP-1 macrophageswith an IC₅₀ of 2.25 μM. This activity, with its inhibition of TNF-α andTH1 cytokines, suggests potential for C17 in the treatment of psoriasis.

TABLE 1 C17 inhibits LPS- and PHA-induced cytokine production by humanPBMCs, as well as IL-23 production when human THP-1 monocytic cells arestimulated with IFN-g and LPS IC50 (mM) Pro-inflammatory Th1 Th2 Com-Cytokines Cytokines Cytokines pounds TNFα IL-1β IL-6 IL-23* IL-2 IFNgIL-5 IL-10 C17 ++++ + + +++ ++++ ++++ +++ ++++ Rolipram ++++ + ++++ ++++++++ ++++ Cilomilast ++++ + ++++ ++++ ++++ +++ + = >30 ++ = 10-29 +++ =1-10 ++++ = <1

TABLE 2 C17 inhibits PDE 4 and PDE7, to a lesser extent PDE1 and PDE3.IC50 (mM) Compound PDE1A3 PDE3 Cat PDE4Cat PDE7A1 C17 +++ +++ ++++ ++++Standard +++ +++ +++ +++ Standards: 8-methoxymethyl-IBMX, Cilostazol,Rolipram and BRL-50481 respectively.

Example 24 In Vivo Activity of C17, a Novel Oxaborole in Development forTreatment of Psoriasis

C17 is a novel boron-containing oxaborole drug with anti-inflammatoryactivity based on the inhibition of the release of pro-inflammatorycytokines including TNF-α, IFN-γ, IL-10, IL-2, IL-4, IL-5, IL-6, IL-8,IL-10, IL-12, and IL-23. C17 also inhibits the release of the chemokineMCP-1 and PGE2. This activity is explained in part by the inhibition ofphosphodiesterase-4 (PDE-4).

A single-center, randomized, vehicle-controlled, observer-blind studyenrolled 12 subjects with psoriasis in order to evaluate theantipsoriatic activity of C17. Six test fields per subject were treated(two active formulations: C17 Ointment, 5%, C17 Cream, 5%, two vehicles,and two comparators).

Study preparation 1 consisted of the C17 Ointment (preparation describedherein), with a topical application of approximately 200 μl ointment pertest field (1.1 cm²) once daily over a 12 day period (10 treatments).The dosage was approximately 10 mg active ingredient/day, for a totaldosage of approximately 100 mg active ingredient.

Study preparation 2 consisted of the C17 Cream (preparation describedherein), with a topical application of approximately 200 μl cream pertest field (1.1 cm²) once daily over a 12 day period (10 treatments).The dosage was approximately 10 mg active ingredient/day, for a totaldosage of approximately 100 mg active ingredient.

Study preparation 3 consisted of the vehicle of study preparation 1 (noC17 present), with a topical application of approximately 200 μl creamper test field (1.1 cm²) once daily over a 12 day period (10treatments).

Study preparation 4 consisted of the vehicle of study preparation 2 (noC17 present), with a topical application of approximately 200 μl creamper test field (1.1 cm²) once daily over a 12 day period (10treatments).

Comparator 1 consisted of Betnesol®-V Creme 0.1%, with topicalapplication of approximately 200 μl cream per test field (1.1 cm²) oncedaily over a 12 day period (10 treatments). The dosage was approximately0.2 mg betamethasone/day, for a total dosage of approximately 2 mgbetamethasone.

Comparator 2 consisted of Protopic® Ointment 0.1%, with topicalapplication of approximately 200 μl cream per test field (1.1 cm²) oncedaily over a 12 day period (10 treatments). The dosage was approximately0.2 mg tacrolimus/day, for a total dosage of approximately 2 mgtacrolimus.

The test preparations were manufactured by Dow Pharmaceutical Sciences,1330A Redwood Way, Petaluma, Calif. 94954, USA. The comparatorBetnesol®-V Creme 0.1% was manufactured by GlaxoWellcome GmbH & Co. Thecomparator Protopic 0.1% was manufactured by Astellas Pharma GmbH,Neumarkter Str. 61, 81673 Munich, Germany. The labeling of the studypreparations was performed at Anacor Pharmaceuticals, 1060 East MeadowCircle, Palo Alto, Calif. 94303-4230, USA.

200 μl of each study preparation and the comparators were applied to thetest fields per treatment. The study preparations were applied underDuring chambers (12 mm inside 0, 14 mm outside Ø) seated in holespunched in a hydrocolloid dressing (Varihesive®, Bristol-Myers SquibbGruppe, Munich, Germany). The amount completely filled the chambers. Thechambers were fixed in place with adhesive patches (Fixomull®, BSN,Hamburg, Germany). In previous studies the hydrocolloid dressing hadbeen shown to be well tolerated. The lack of a therapeutic influence ofthe dressing on the psoriasis had been verified by determination of theinfiltrate thickness before and after application. The distance betweenchambers had to be at least 1.5 cm. This distance was sufficient toexclude interactions with neighboring fields. All fields were treatedunder occlusion 10 times over 12 days. Before each new applicationremaining preparation residues were removed by gently cleansing eachtest field with a separate soft tissue. On 10 of the study daystreatments were performed (days 1-6 and 8-11). The hydrocolloid dressingstayed in place for maximal 7 days, it was renewed on study day 8.

Experimental measurements included sonography, photo documentation andclinical assessments with intra individual comparison of the treatments.

On the first day of the study the outline of the plaque was traced ontoa transparent plastic sheet. The intended test fields were then drawn onthe sheet, taking care to allow at least 1.5 cm between sites. The testfields were numbered from 1-6. The plastic sheets were attached to thecase report form (CRF). Baseline sonographic measurements andphotodocumentation were performed. Pretreatment clinical assessmentscores were 0 by definition in all test fields. The hydrocolloiddressing was attached and the first treatment performed as describedabove.

On study days 2 to 6 and 8 to 11 the occluding chambers were removed andtreatments renewed once daily. On study day 7 dressing and chambersremained in place until study day 8. On study days 8 and 12 thehydrocolloid dressing was also removed and sonography, clinicalassessment and photodocumentation performed after removal of preparationresidues. On the last day of the study the final clinical examinationwas made including safety laboratory testing (hematology, clinicalchemistry and urinalysis).

Sonographic measurements were performed using a 20 MHz high frequencysonograph (DUB 20S, Taberna pro Medicum, Lueneburg). Serial A-scans werecomposed and represented on a monitor as a section of the skin. Alateral resolution of approximately 200 μm and an axial resolution of 80μm are possible. Dependent on the echo patterns, components of theepidermis, dermis and subcutis were represented. Therefore exactmeasurement of skin thickness was possible. The inflammatory psoriaticinfiltrate was seen as a clearly definable echo lucent band below theentrance echo. The thickness of the echo lucent psoriatic band wasdetermined and documented. The thickness was measured in μm and wasdenoted as T.

Clinical assessment (global assessment) of the test fields was performedusing a 5-point score: −1=worsened; 0=unchanged (no effect); 1=slightimprovement; 2=clear improvement but not completely healed; 3=completelyhealed. Comparison was made with the untreated plaque beneath thehydrocolloid dressing. Clinically apparent differences in erythema andinfiltration contributed to this global assessment.

The infiltrate thickness showed that treatment with C17 led to arelevant and clear improvement. The mean percent reduction in infiltratethickness for both C17-formulations was 54% vs. no changes in the meaninfiltrate thickness for the vehicles. The statistical comparisonsshowed that C17, 5% demonstrated a significantly higher reduction(p<0.025) in infiltrate thickness than the corresponding vehicles. Forthe comparator Protopic™ Ointment 0.1% the mean percent reduction ininfiltrate thickness (48%) was lower. A higher reduction in the meaninfiltrate thickness (72%) was noted for the comparator Betnesol™-VCreme, 0.1%. No significant differences were found between the C17Ointment, 5% and the Betnesol™-V Creme 0.1% on study day 12. In allother comparisons Betnesol™-V Creme 0.1% demonstrated a significantlyhigher reduction in infiltrate thickness. The clinical assessments andother secondary endpoints paralleled the findings of the sonographicmeasurements.

Example 25 C27, a Novel Oxaborole Compound with Anti-InflammatoryActivity Results of in Vivo Efficacy and Preclinical Safety Studies

C27 is the second in a series of novel oxaborale compounds thatdecreases TNFα release through potent inhibition of phosphodiesterase 4(PDE4). This new drug is currently in preclinical development forpsoriasis and atopic dermatitis. C27 demonstrates significant in vivoactivity in a model of acute skin irritation. In an acetone/ethanolvehicle, 5% C27 inhibits PMA induced ear edema greater than 15%dexamethasone (82% vs 73% inhibition, respectively, p<0.01) and isactive in this model in an ointment vehicle at concentrations as low as0.01%. Topical C27 also significantly inhibits oxazolone induced earswelling (a model of allergic contact dermatitis). In vitro screeningshows C27 to have no significant hERG or p450 enzyme inhibition.Pharmacokinetic analysis in the rat after oral dosing at 100 mg/kgdemonstrates relatively low bioavailability (7%) and, after intravenousdosing at 20 mg/kg, a mean plasma residence time of 0.64 h. C27 is safein a rat 14-day oral repeated dose study at 10, 100, and 300 mg/kg/day;no clinical chemistry or hematology effects were seen at any dose. Italso shows less emetic effect than rolipram. The no effect Cmax plasmalevel of C27 in a shrew emesis assay was 12.4 μg/ml. Dermal applicationof 5% C27 ointment or cream over 15% body surface area on the Göttingenminipig results in undetectable plasma levels of the compound (LLOQ=0.01μg/ml) and no dermal irritation after 24 hours of exposure. These earlystudies suggest that C27 has the required in vivo biological activityand good preclinical safety profile to enable clinical trials.

Example 26 Structure-Activity Studies of C17 and C27, Novel OxaboroleCompounds with Anti-Inflammatory Activity

The structure-activity relationships of novel boron-containinganti-inflammatory agents was investigated. C17(5-(4-cyanophenoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole) is a broadspectrum anti-inflammatory compound that is currently under developmentfor the topical treatment of plaque psoriasis. C17 inhibited release ofTNF-alpha from peripheral blood mononuclear cells (PBMCs) stimulated bylipopolysaccharide (LPS). C17 was found to inhibit the phosphodiesterase4 (PDE4) enzyme derived from human U937 cells. Since the PDE4 inhibitionwas considered to be a part of its mechanism of action to inhibit theTNF-alpha release, investigation of structure-activity relationshipsaround this compound was carried out to identify a more potentPDE4/TNF-alpha inhibitor.

Compounds were screened by a biochemical assay against PDE4 enzyme andcell-based cytokine release assays using PBMCs stimulated by LPS orphytohemagglutinin (PHA). The results showed that electron-withdrawinggroups, such as cyano and N,N-dialkylcarbamoyl, at the para-position tothe oxygen atom were important for the activity. Ester and pyridineanalogs also showed potent activity. However, carboxy derivatives lostmost of the activity in both assays. C27 showed potent inhibitionagainst PDE4 (IC₅₀ 60 nM), while the IC₅₀ of C17 and rolipram were 490nM and 860 nM, respectively. The regioisomers of the cyano group wereless active. C27 also inhibited the release of cytokines, such asTNF-alpha (IC₅₀ 160 nM), IL-2 (IC₅₀ 180 nM), and interferon-gamma (IC₅₀220 nM). C27 did not show cytotoxicity against L929 and HepG2 cell linesup to 100 micro M.

Example 27 Ointment Formulations for C17 or C27

In the manufacturing vessel, add the required amounts of whitepetrolatum and heat to melt at 65±5° C. In stainless steel vessel, addC17 or C27, oleyl alcohol and Octyl hydroxystearate Propeller mix whileheating to 65±5° C. until a clear solution (suspension in case of 5%C17) is obtained. Maintain the temperature. With Homogenizer mixing, addthe C17 or C27 mixture to the manufacturing vessel. Homogenize at 65±5°C. for a minimum of 5 minutes. Remove the heat source and start cooling.Continue mixing until the ointment is homogenous.

The composition of an C17 ointment is provided below.

Quantitative Composition of C17 Ointment, 0.5%, 2% and 5%

Component % w/w % w/w % w/w C17 0.5 2.0 5.0 Ethylhexyl Hydroxystearate10.0 10.0 10.0 Oleyl Alcohol 10.0 10.0 10.0 White Petrolatum 79.5 78.075.0

The composition of an C27 ointment is provided below.

Quantitative Composition of C27 Ointment, 0.01, 0.1%, 1% and 2%

Component % w/w % w/w % w/w % w/w C27 0.01 0.1 1.0 2.0 EthylhexylHydroxystearate 10.0 10.0 10.0 10.0 Oleyl Alcohol 10.0 10.0 10.0 10.0White Petrolatum 79.99 79.90 79.0 78.0

Example 28 C17 Cream Formulations Cream Formulation A for C17

In stainless steel (SS) vessel 1, add purified water and Glycerin forpreparation of Xanthum gum blend. With propeller mixing, add Xanthum Gumand mix until a smooth and uniform gel is formed. In stainless steelvessel 2, add purified Water and Sodium Hydroxide and mix with a stirbar until a clear 10% Sodium Hydroxide Solution is obtained. Instainless steel vessel 3, add C17, Oleyl Alcohol, EthylhexylHydroxystearate, Glyceryl Monostearate SE, Cholesterol, and ButylatedHydroxytoluene. Propeller mix while heating to 80±5° C. until a clearsolution is obtained. Maintain the temperature. With Homogenizer mixing,add the solution from SS Vessel 3 into the Manufacturing Vessel.Homogenize at 80±5° C. for a minimum of 5 minutes. Remove the heatsource and start cooling. Continue with propeller mixing until a thincream is formed and it reaches 30-35° C. With Homogenizer mixing, addthe Xanthum Gum Blend from SS Vessel 1. Continue with Homogenizationuntil the cream becomes thicker, smooth and homogeneous. Adjust pH ofthe cream with either 10% Sodium Hydroxide Solution or DilutedHydrochloric Solution to pH 6.0±0.3. QS the batch to 100% with remainingamount of Purified Water. Mix with a propeller until the cream is smoothand homogeneous.

The composition of an C17 cream is provided below.

Cream Formulation A for C17, 5%

Component % w/w C17 5.0 Methylparaben 0.15 Propylparaben 0.03 PropyleneGlycol 5.0 Glycerol Monostearate SE 7.0 Cholesterol 0.8 Oleyl Alcohol10.0 Butylated Hydroxytoluene 0.1 Ethylhexyl Hydroxystearate 12.0Xantham Gum Blend 15.0 Citric Acid, anhydrous 0.12 Sodium Citrate,anhydrous 1.39 10% Sodium Hydroxide Solution q.s. pH 6.0 DiluteHydrochloric Acid q.s. pH 6.0 Purified Water, (for Xanthum Gum Blend)40.0 Purified Water, (for the entire composition) q.s. 100%

Xantham Gum Blend

Component % w/w Xantham Gum 3.0 Glycerin 5.0 Purified Water 92.0

10% Sodium Hydroxide Solution

Component % w/w Sodium Hydroxide 10.0 Purified Water 90.0

Cream Formulation B for C17

In a stainless steel vessel, add oleyl alcohol, benzyl alcohol,diisopropyl adipate, glyceryl monostearate SE, octyldodecanol, butylatedhydroxytoluene and C17. Propeller mix while heating to 60±5° C. until aclear solution is obtained. Maintain the temperature. With continuouspropeller mixing, add pemulen TR-2. Mix until the oily components arevisually homogeneous. Maintain the temperature. In a manufacturingvessel, add purified water, methylparaben, propylparaben, propyleneglycol, and edetate disodium. Propeller mix while heating to 60±5° C.until a clear solution is obtained. Maintain the temperature.

With continuous propeller mixing, add carbopol ultrez 10. Mix until theaqueous phase is visually homogeneous. Maintain the temperature. Withhomogenizer mixing, add the oil phase into the aqueous phase in themanufacturing vessel. Homogenize at 60±5° C. for a minimum of 5 minutes.Remove the heat source and start cooling. Continue with propeller mixingand add 25% trolamine and mix until the cream becomes thicker, smoothand reaches room temperature.

The composition of another C17 cream is provided below.

Cream Formulation B for C7, 0.3-2%

Component % w/w % w/w % w/w C17 0.3 1.0 2.0 Methylparaben 0.15 0.15 0.15Propylparaben 0.03 0.03 0.03 Glyceryl Monostearate SE 8.0 8.0 8.0Butylated Hydroxytoluene 0.02 0.02 0.02 Edetate Disodium 0.05 0.05 0.05Pemulen TR-2 0.25 0.25 0.25 Carbopol Ultrez 10 0.20 0.20 0.20 25%Trolamine 0.84 0.84 0.84 Propylene Glycol 5.0 5.0 5.0 Octyldodecanol10.0 10.0 10.0 Oleyl Alcohol 10.0 10.0 10.0 Benzyl Alcohol 2.0 2.0 2.0Diisopropyl Adipate 10.0 10.0 10.0 Purified Water QS 100 QS 100 QS 100

25% Trolamine Solution

Component % w/w Trolamine 25.0 Purified Water 75.0

Example 29 C27 Cream Formulation

In a stainless steel vessel, add Benzyl alcohol, Octyldodecanol, C27,Stearyl alcohol, Cetyl alcohol, BHT and Glyceryl monostearate. Propellermix while heating to 65±5° C. until the solids have melted and ahomogenous solution appears Maintain the temperature. In themanufacturing vessel, add purified water, Polysorbate 60, Propyleneglycol, Methyl paraben, Propyl paraben and edetate sodium. Heat to 65±5°C. while mixing with a homogenizer until a clear solution is obtainedMaintain the temperature. With homogenizer mixing, add the C27 oil phasecomponents to the aqueous phase in the manufacturing vessel. Homogenizeat 65±5° C. for a minimum of 5 minutes. Remove the heat source and startcooling. Continue with propeller mixing until the cream becomes thicker,smooth and reaches room temperature.

The composition of an C27 cream is provided below.

Component % w/w % w/w % w/w % w/w C27 0.01 0.1 1.0 2.0 Benzyl alcohol1.0 1.0 1.0 1.0 BHT 0.01 0.01 0.01 0.01 Octyldodecanol 13.5 13.5 13.513.5 Glyceryl monostearate 8.0 8.0 8.0 8.0 Stearyl alcohol 10.0 10.010.0 10.0 Cetyl alcohol 5.0 5.0 5.0 5.0 Polysorbate -60 3.0 3.0 3.0 3.0Methyl paraben 0.15 0.15 0.15 0.15 Propyl paraben 0.03 0.03 0.03 0.03Edetate Disodium 0.05 0.05 0.05 0.05 Propylene glycol 5.0 5.0 5.0 5.0Purified Water QS 100 QS 100 QS 100 QS 100

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A compound having a structure according to theformula:

wherein R^(a) is a member selected from CN, C(O)NR¹R², C(O)OR³ whereinR³ is a member selected from H and substituted or unsubstituted alkyl, Xis a member selected from N, CH and CR^(b), R^(b) is a member selectedfrom halogen and substituted or unsubstituted alkyl, C(O)R⁴, C(O)OR⁴,OR⁴, NR⁴R⁵, wherein R¹, R², R⁴ and R⁵ are members independently selectedfrom H, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl, with the proviso that R¹ andR², together with the atoms to which they are attached, are optionallycombined to form a 4- to 8-membered substituted or unsubstitutedheterocycloalkyl ring with the proviso that R⁴ and R⁵, together with theatoms to which they are attached, are optionally combined to form a 4-to 8-membered substituted or unsubstituted heterocycloalkyl ring, andsalts thereof.
 2. The compound of claim 1, wherein R³ is a memberselected from H and unsubstituted alkyl.
 3. The compound of claim 1, thecompound has a structure according to the formula:


4. The compound of claim 1, the compound has a formula which is a memberselected from:


5. The compound of claim 1, the compound has a formula which is a memberselected from:


6. The compound of claim 1, the compound has a formula which is a memberselected from:


7. The compound of claim 1, the compound has a formula which is a memberselected from:


8. The compound of claim 1, the compound has a structure according tothe formula:


9. The compound of claim 1, the compound has a formula which is a memberselected from:


10. The compound of claim 1, the compound has a formula which is amember selected from:


11. The compound of claim 1, the compound has a formula which is amember selected from:


12. The compound of claim 1, the compound has a formula which is amember selected from:


13. The compound of claim 1, the compound has a structure according tothe formula:


14. The compound of claim 1, the compound has a formula which is amember selected from:


15. The compound of claim 1, the compound has a formula which is amember selected from:


16. The compound of claim 1, the compound has a formula which is amember selected from:


17. The compound of claim 1, the compound has a formula which is amember selected from:


18. The compound of claim 1, wherein R^(b) is a member selected fromfluorine and chlorine.
 19. The compound of claim 1, wherein R^(b) is amember selected from OR⁴ and NR⁴R⁵.
 20. The compound of claim 1, whereinR^(b) is OR⁴, and R⁴ is a member selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.
 21. The compound of claim 1, wherein R^(b) isOR⁴, and R⁴ is a member selected from H, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl and substituted orunsubstituted cycloalkyl.
 22. The compound of claim 1, wherein R^(b) isOR⁴, and R⁴ is unsubstituted C₁-C₆ alkyl.
 23. The compound of claim 1,wherein R^(b) is OR⁴, and R⁴ is unsubstituted cycloalkyl.
 24. Thecompound of claim 1, wherein R^(b) is OR⁴, and R⁴ is alkyl, substitutedwith a member selected from substituted or unsubstituted C₁-C₆ alkoxy.25. The compound of claim 1, wherein R^(b) is OR⁴, and R⁴ is alkyl,substituted with at least one halogen.
 26. The compound of claim 1,wherein R^(b) is OR⁴, and R⁴ is alkyl, substituted with at least one oxomoiety.
 27. The compound of claim 1, wherein R^(b) is OR⁴, and R⁴ is amember selected from —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —CH(CH₃)₂, —CH₂CF₃,—CH₂CHF₂, —CH₂CH₂(OH), —CH₂CH₂(OCH₃), —CH₂CH₂(OC(CH₃)₂), —C(O)CH₃,—CH₂CH₂OC(O)CH₃, —CH₂C(O)OCH₂CH₃, —CH₂C(O)OC(CH₃)₃, —(CH₂)₃C(O)CH₃,—CH₂C(O)OC(CH₃)₃, cyclopentyl, cyclohexyl


28. The compound of claim 1, wherein R^(b) is NR⁴R⁵, wherein R⁴ and R⁵are members independently selected from H, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.
 29. The compound of claim 28, wherein R^(b) is NR⁴R⁵,wherein R⁴ is H or unsubstituted alkyl; and R⁵ is unsubstituted alkyl oralkyl substituted with a member selected from hydroxyl, phenyl,unsubstituted alkoxy and alkoxy substituted with a phenyl.
 30. Thecompound of claim 29, wherein R^(b) is NR⁴R⁵, wherein R⁴ is a memberselected from H or CH₃.
 31. The compound of claim 28, wherein R^(b) isNR⁴R⁵, wherein R⁴ and R⁵ are each members independently selected fromsubstituted or unsubstituted alkyl.
 32. The compound of claim 28,wherein R^(b) is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl; and R⁵ issubstituted or unsubstituted alkyl.
 33. The compound of claim 28,wherein R^(b) is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl; and R⁵ isalkyl, substituted with a member selected from substituted orunsubstituted alkoxy and hydroxyl.
 34. The compound of claim 28, whereinR^(b) is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl; and R⁵ is alkyl,substituted with unsubstituted alkoxy.
 35. The compound of claim 28,wherein R^(b) is NR⁴R⁵, wherein R⁴ is unsubstituted alkyl; and R⁵ isalkyl, substituted with alkoxy, substituted with phenyl.
 36. Thecompound of claim 28, wherein R^(b) is NR⁴R⁵, wherein R⁴ isunsubstituted alkyl; and R⁵ is alkyl, substituted with unsubstitutedalkoxy.
 37. The compound of claim 28, wherein R^(b) is a member selectedfrom N(CH₃)₂, N(CH₃)(CH₂CH₂(OCH₃)), N(CH₃)(CH₂CH₂OH), NH₂, NHCH₃,NH(CH₂CH₂(OCH₃)), NH(CH₂CH₂(OCH₂Ph), NH(CH₂Ph), NH(C(CH₃)₃) andNH(CH₂CH₂OH).
 38. The compound of claim 1, wherein R^(b) is NR⁴R⁵,wherein R⁴ and R⁵, together with the nitrogen to which they areattached, are combined to form a 4- to 8-membered substituted orunsubstituted heterocycloalkyl ring.
 39. The compound of claim 38,wherein R^(b) is NR⁴R⁵, wherein R⁴ and R⁵, together with the nitrogen towhich they are attached, are combined to form a 5- or 6-memberedsubstituted or unsubstituted heterocycloalkyl ring.
 40. The compound ofclaim 1, wherein R^(b) is a member selected from:


41. A pharmaceutical formulation comprising: (a) the compound of claim1; (b) a pharmaceutically acceptable excipient.
 42. The formulation ofclaim 41, wherein the formulation is in a unit dosage form.
 43. Theformulation of claim 41, wherein the formulation is for oral or topicaluse.
 44. A method of decreasing the release of a cytokine or achemokine, the method comprising: contacting a cell with the compound ofclaim 1 or a pharmaceutically acceptable salt thereof, wherein therelease of the cytokine or chemokine by the cell is decreased.
 45. Themethod according to claim 44, wherein the cytokine is a member selectedfrom IL-1α, IL-1β, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18,IL-23, TNF-α, LT, LIF, Oncostatin, IFNα, IFNβ and IFN-γ.
 46. The methodaccording to claim 44, wherein the cytokine is a member selected fromIL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-23, TNF-α andIFN-γ.
 47. The method according to claim 44, wherein the cytokine is amember selected from IL-2, IL-5, IL-10, IL-12, IL-23, TNF-α and IFN-γ.48. The method according to claim 44, wherein the chemokine is a memberselected from IL-8, Gro-α, MIP-1, MCP-1, PGE2, ENA-78, and RANTES.
 49. Amethod of treating a condition, in an animal, the method comprisingadministering to the animal a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof,thereby treating the condition.
 50. The method of claim 49, wherein thecondition is a member selected from arthritis, rheumatoid arthritis, aninflammatory bowel disease, psoriasis, a pulmonary disease, multiplesclerosis, a neurodegenerative disorder, congestive heart failure,stroke, aortic valve stenosis, kidney failure, lupus, pancreatitis,allergy, fibrosis, anemia, atherosclerosis, a metabolic disease, a bonedisease, a cardiovascular disease, a chemotherapy/radiation relatedcomplication, diabetes type I, diabetes type II, a liver disease, agastrointestinal disorder, an ophthamological disease, allergicconjunctivitis, diabetic retinopathy, Sjogren's syndrome, uvetitis, apulmonary disorder, a renal disease, dermatitis, HIV-related cachexia,cerebral malaria, ankylosing spondolytis, leprosy, anemia andfibromyalgia.
 51. The method of claim 50, wherein the condition is amember selected from psoriasis, atopic dermatitis, rheumatoid arthritis,an inflammatory bowel disease, asthma and chronic obstructive pulmonarydisease.
 52. The method of claim 50, wherein the condition is psoriasis,said psoriasis is a member selected from plaque psoriasis, flexuralpsoriasis, Guttate psoriasis, pustular psoriasis, nail psoriasis anderythrodermic psoriasis.
 53. The method of claim 52, wherein thepsoriasis is a member selected from plaque psoriasis and nail psoriasis.54. A method of inhibiting a phosphodiesterase (PDE), the methodcomprising: contacting the phosphodiesterase with a compound of claim 1or a pharmaceutically acceptable salt thereof, thereby inhibiting thephosphodiesterase.
 55. The method of claim 54, wherein saidphosphodiesterase is a member selected from phosphodiesterase4 (PDE4)and phosphodiesterase7 (PDE7).